Substituted pyrazolopyrimidines and method of use

ABSTRACT

Compounds of formula (I) 
                         
and pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , R 4 , L 1  and G 1  are as defined in the specification, are useful in treating conditions or disorders prevented by or ameliorated by positive allosteric modulation of the γ-aminobutyric acid B (GABA-B) receptor. Methods for making the compounds are described. Also described are pharmaceutical compositions of compounds of formula (I), and methods for using such compounds and compositions.

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

This patent application claims priority to International PatentApplication No. PCT/CN2015/076978 filed on Apr. 20, 2015, and EuropeanPatent Application No. 15168924.7 filed May 22, 2015. The entirecontents of these applications are incorporated by reference into thispatent application.

BACKGROUND OF THE INVENTION

Technical Field

The invention relates to substituted pyrazolopyrimidines that arepositive allosteric modulators of the γ-aminobutyric acid receptor(e.g., GABA-B PAM), useful in treating diseases and conditions mediatedand modulated by the γ-aminobutyric acid receptor B. Additionally, theinvention relates to compositions containing compounds of the inventionand processes of their preparation.

Description of Related Technology

The inhibitory neurotransmitter, γ-aminobutyric acid (GABA) exerts itsactions through three distinct receptors—the ionotropic GABA-A andGABA-C receptors, and the metabotropic GABA-B receptor. The GABA-Breceptor is a member of the class C family of GPCRs. The GABA-B receptoris an obligate heterodimer composed of a GABA-B1 and a GABA-B2 subunit(Bettler, B., et al. Physiol Rev 2004; 84: 835-867). Notably,heterodimerization of the B1 and B2 subunits is required for properGABA-B receptor expression and function (Pin, J. P., et al. BiochemPharmacol 2004; 68: 1565-1572). Agonist binding to the B1 subunit of theGABA-B heterodimer results in transactivation of the B2 subunit andsubsequent stimulation of G_(i/o) proteins. This, in turn, activates K⁺currents, inhibits Ca²⁺ currents, and decreases cAMP via negativeregulation of adenylyl cyclase.

GABA-B receptor subunits are found both pre- and post-synapticallythroughout the CNS and the periphery, with highest expression in thethalamus, cortex, cerebellum and dorsal horn (Fritschy, J. M., et al.Eur J Neurosci 1999; 11: 761-768). Functional receptor expressionappears to be limited by the presence of the GABA-B2 subunit, which isoften detected at lower levels than the B1 subunits (Bowery, N. G. AdvPharmacol 2010; 58: 1-182). Therapeutically, the beneficial effects ofGABA-B receptor stimulation include muscle relaxation, substance abusetreatment (especially in alcohol dependence), antinociception,spasticity, fragile X syndrome, Down's syndrome, autism, retinalganglion cell degeneration, gastro-esophageal reflux disease (GERD),smoking cessation, addiction of narcotic agents, emesis, cough,overactive bladder, anxiety, migraine or tinnitus. The in vivoconsequence of GABA-B activation has been confirmed experimentally withknockout mouse models, which are hyperalgesic, and clinically with theGABA-B orthosteric agonist, baclofen (Slonimski, M., et al. Reg AnesthPain Med 2004; 29: 269-276. Bowery, N. G., et al. Pharmacol Rev 2002;54: 247-264). Unfortunately, the utility of baclofen is limited by drugtolerance and severe side effects, including hypothermia, seizures,sedation and cognitive deficits. Baclofen has poor brain penetrance andrequires high doses for engagement of CNS GABA-B receptors, resulting inelevated plasma concentrations. Peripheral GABA-B receptors on smoothand skeletal muscle are activated by these high plasma concentrationsand appear to mediate a subset of baclofen side effects, includinghypothermia and seizures that are hypothesized to arise from erraticmuscle contractions. Drug tolerance requiring dose escalation has beenreported three to seven days after initiation of baclofen and mostlikely arises from receptor desensitization (Sands, S. A., et al. JPharmacol Exp Ther 2003; 305: 191-196). This reduction in GABA-Breceptor signaling mimics the genotype of GABA-B knockout mice, whichalso exhibit severe cognitive and learning deficits (Schuler, V., et al.Neuron 2001; 31: 47-58). Tolerance and receptor desensitizationfollowing repeated baclofen administration may therefore underlie thecognitive deficits and learning impairments associated with baclofentreatment. Finally, abrupt discontinuation of intrathecal baclofenresults in severe withdrawal symptoms, including seizures (Ross, J. C.,et al. Neurocrit Care 2011; 14: 103-108). This indicates an underlyingchange in the physiological balance of GABA neurotransmitter and GABA-Breceptor after continued exogenous agonist stimulation. Similarly, theGABA-B knockout mouse exhibits epileptiform seizures, furtherunderscoring the importance of maintaining the normal, physiologicalGABA-B tone within the CNS. While the GABA-B receptor remains a validdrug target, the side effects and tolerance associated with baclofenemphasize the need to pursue alternatives to classic orthostericactivation of the receptor.

To exploit the beneficial aspects of GABA-B stimulation, the disclosuredescribes positive allosteric receptor ligands for modulation of theGABA-B receptor. Positive allosteric modulators alter the receptorconformation and enhance the activity of the endogenous orthostericagonist, either by increasing the affinity or the efficacy of theorthosteric ligand at the receptor (Wang, L., et al. J Pharmacol ExpTher 2009; 331: 340-348). Because allosteric modulators rely on locallevels of endogenous ligand and have little or no activity of their own,they are thought to represent a safer and more subtle means of receptorregulation. The hypothesis is that GABA-B receptor allostericmodulators, and possibly allosteric agonists, will be effectivetherapeutic agents while minimizing the side effects caused by agonistactivation of the orthosteric GABA-B site. In addition to painindications (Anghinah, R., et al. Muscle Nerve 1994; 17(8): 958-959.Fromm G. H., et al. Ann. Neuro. 1984; 15: 240-244.), GABA-B modulatorscould also be used in the treatment of depression, spasticity (Bowery,N. G. Curr Opin Pharmacol 2006; 6; 37-433. Froestl, W. Expert Opin TherPat 2010; 20: 1007-1017. Ong, J., et al. CNS Drug Rev 2005; 11:317-334.)), fragile X syndrome (Lozano, R., et al. NeuropsychiatricDisease and Treatment 2014; 10: 1769-1779), Down's syndrome(Kleschevnikov, A. M., et al. Journal of Neuroscience 2012; 32(27):9217-9227), autism (Oblak, A. L., et al. Journal of Neurochemistry 2010;114(5): 1414-23), retinal ganglion cell degeneration (Hirano, A. A., etal. Journal of Comparative Neurology 2005; 488(1): 70-81),gastro-esophageal reflux disease (GERD) (Lacy, B. E., et al. Drugs ofthe Future 2010; 35(12): 987-992. Boeckxstaens, C. E. et al. CurrentOpinion in Pharmacology 2008; 8(6): 685-689. Lehmann, A., et al.Advances in Pharmacology 2010; 58: 287-313) smoking cessation (Vlachou,S., et al. Psychopharmacology 2011; 215(1): 117-128), addiction ofnarcotic agents (Spano, M. S., et al. Neuropharmacology 2007; 52(7):1555-62), emesis (Sanger, G. J., et al. Autonomic Neuroscience 2006;129(1-2): 3-16), cough (Bolser, D. C., et al. British Journal ofPharmacology 1993; 110(1): 491-495), overactive bladder (Taylor, M. C.,et al. British J. Urology 1979; 51: 504-505), anxiety (Krupitsky, E. M.,et al. Drug and Alcohol Dependence 1993; 33: 157 163. Cryan, J. F., etal. J Pharmacol Exp Ther 2004; 310: 952-963. Mombereau, C., et al.Neuropsychopharmacology 2004; 29: 1050-1062), migraine (Hering-Hanit,R., Cephalalgia 1999; 19(6): 589-91. Hering-Hanit, R., et al. Headache2000; 40(1): 48-51.), and tinnitus (Smith, P. F., et al. Frontiers inNeurology 2012; 3: 34). Positive allosteric modulators (PAMs) bind tofunctionally and topographically distinct allosteric sites on thereceptor and act at a distance from the orthosteric site to enhance theefficacy of the endogenous ligand. A single receptor may possessmultiple, discrete allosteric sites, each with a unique subset ofligands. Pure PAMs are devoid of activity on their own they will onlyenhance the potency and/or efficacy of the endogenous agonist thus theirpharmacological profile is spatially and temporally controlled by thenormal physiological interaction between the endogenous ligand and itsreceptor. This highlights a critical difference between PAMs andorthosteric agonists PAMs avoid the maximum on/off at all receptors thatoccurs with classic orthosteric agonist stimulation. Because PAMs relyon endogenous agonist concentrations for activity, they promotefine-tuning of the GABA signal in a physiologically-relevant manner.Importantly, GABA-B PAMs do not cause receptor desensitization (Gjoni,T., et al. Neuropharmacology 2008; 55: 1293-1299), so the clinicaltolerance and side effects related to receptor desensitization that areobserved with baclofen are unlikely to occur. Finally, the majority ofGABA-B PAMs tested in the literature (Brusberg, M., et al.Neuropharmacology 2009; 56: 362-367. Froestl, W. Expert Opin Ther Pat2010; 20: 1007-1017. Koek, W., et al. J Pharmacol Exp Ther 2010; 335:163-17. Pin, J. P., et al. Curr Neuropharmacol 2007; 5, 195-201.) showgreatly enhanced brain penetrance as compared to baclofen and excellentefficacies in preliminary studies with minimum or no side effects. Thesecollective data emphasize the need for alternative therapeutics at theGABA-B receptor, and highlight the unique ability of PAMs to stimulatethe receptor without baclofen-like side effects.

SUMMARY

The invention is directed to substituted pyazolopyrimidines having astructure of formula (I)

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from the group consisting of C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₃-C₆cycloalkyl, C₃-C₆cycloalkylC₁-C₆alkyl, 4-7-memberedheterocycle and 4-7-membered heterocycleC₁-C₆alkyl, wherein each of the4-7-membered heterocycles in the two last mentioned radicals aresaturated or have one endocyclic double bond;

-   -   a) the C₁-C₆alkyl, the C₂-C₆alkenyl, the C₂-C₆alkynyl, the        C₁-C₆alkyl of C₃-C₆cycloalkylC₁-C₆alkyl, and the C₁-C₆alkyl of        4-7-membered heterocycleC₁-C₆alkyl are unsubstituted or        substituted with one or more, e.g. 1, 2, 3, 4 or 5, substituents        R^(1a) independently selected from the group consisting of        C₁-C₆alkoxy, C₁-C₆alkylcarbonylamino, C₁-C₆alkylsulfonylamino,        amido, carboxy, cyano, halogen, hydroxy, and oxo;    -   b) the C₃-C₆cycloalkyl, the C₃-C₆cycloalkyl of        C₃-C₆cycloalkylC₁-C₆alkyl, 4-7-membered heterocycle, and the        4-7-membered heterocycle of 4-7-membered heterocycleC₁-C₆alkyl        are unsubstituted or substituted with one or more, e.g. 1, 2, 3,        4, 5 or 6, substituents R^(1b) independently selected from the        group consisting of C₁-C₆alkoxy, C₁-C₆alkyl, amido,        C₁-C₆alkylcarbonylamino, C₁-C₆alkylsulfonylamino, carboxy,        cyano, halogen, haloC₁-C₆alkyl, hydroxy, hydroxyC₁-C₆alkyl, and        oxo;

R² is selected from the group consisting of hydrogen, C₁-C₆alkyl, andhaloC₁-C₆alkyl; or

R¹, R² and the nitrogen to which they are attached form a saturated4-7-membered N-bound heterocycle, which in addition to the nitrogen atommay have one further heteroatom selected from O, S and N as a ringmember, wherein:

-   -   each such 4-7-membered heterocycle is unsubstituted or        substituted with one or more, e.g. 1, 2, 3, 4, 5 or 6, identical        or different substituents R^(1c), where R^(1c) is selected from        the group consisting of C₁-C₆alkoxy, C₁-C₆alkyl,        C₁-C₆alkylcarbonylamino, C₁-C₆alkylsulfonylamino, amido,        carboxy, cyano, halogen, haloC₁-C₆alkyl, amino, hydroxy,        hydroxyC₁-C₆alkyl, oxo, spirocyclic bound C₃-C₆cycloalkyl; and        spirocyclic bound saturated 4-6-membered heterocycle; wherein        -   each spirocyclic bound C₃-C₆cycloalkyl and spirocyclic bound            4-6-membered heterocycle is unsubstituted or substituted            with one or more substituents independently selected from            the group consisting of C₁-C₆alkyl, cyano, halogen,            haloC₁-C₆alkyl, hydroxy, and hydroxyC₁-C₆alkyl;

R³ is hydrogen, C₁-C₆alkyl, or haloC₁-C₆alkyl;

R⁴ is hydrogen, C₁-C₆alkyl, or haloC₁-C₆alkyl; or

R³ and R⁴ are joined to form a C₃-C₇alkylene;

L¹ is selected from the group consisting of —(CR⁵R⁶)_(m)—,—(CH₂)_(n)CR^(5a)═CR^(6a)(CH₂)_(p)—, and

wherein

-   -   c) R⁵, R^(5a), R^(5b), R⁶, R^(6a) and R^(6b) are, at each        occurrence, independently selected from the group consisting of        hydrogen, C₁-C₆alkyl, fluorine, haloC₁-C₆alkyl and phenyl,        wherein;        -   phenyl is unsubstituted or substituted with one or more,            e.g. 1, 2, 3, 4 or 5, substituents selected from the group            consisting of C₁-C₆alkyl, halogen, and haloC₁-C₆alkyl; or    -   d) R⁵ or R⁶ is a C₂-C₄alkylene attached to G′;    -   e) m is 1, 2, 3 or 4;    -   f) n is, at each occurrence, independently 0, 1, or 2;    -   g) p is, at each occurrence, independently 0, 1, or 2; and

G¹ is selected from the group consisting of C₅-C₁₀cycloalkyl,5-6-membered heteroaryl, 5-6-membered heterocycle, which is saturated orhas one endocyclic double bond, and phenyl; wherein

-   -   each C₅-C₁₀cycloalkyl, 5-6-membered heteroaryl, 5-6-membered        heterocycle, and phenyl is unsubstituted or substituted with one        or more, e.g. 1, 2, 3, 4 or 5, identical or different        substituents R^(G), where R^(G) is selected from the group        consisting of C₁-C₆alkyl, cyano, haloC₁-C₆alkyl, halogen,        C₁-C₆alkoxy and haloC₁-C₆alkoxy.

Another aspect of the invention relates to pharmaceutical compositionscomprising compounds of the invention. Such compositions can beadministered in accordance with a method of the invention, typically aspart of a therapeutic regimen for treatment or prevention of conditionsand disorders related to γ-aminobutyric acid receptor B (GABA-B)activity.

Yet another aspect of the invention relates to a method of enhancing theactivity of the endogenous orthosteric agonist by altering the GABA-Breceptor conformation by treatment at an allosteric binding site with apositive allosteric modulator. The method is useful for treating, orpreventing conditions and disorders related to pain, substance abuse(especially in alcohol dependence), spasticity, fragile X syndrome,Down's syndrome, autism, retinal ganglion cell degeneration,gastro-esophageal reflux disease (GERD), smoking cessation, addiction ofnarcotic agents, emesis, cough, overactive bladder, anxiety, migraineand tinnitus in mammals. Accordingly, the compounds and compositions ofthe invention are useful as a medicament for treating or preventingγ-aminobutyric acid receptor B modulated disease.

The compounds, compositions comprising the compounds, methods for makingthe compounds, and methods for treating or preventing conditions anddisorders by administering the compounds are further described herein.

In a particular aspect, the compounds of the invention are provided foruse in the treatment of pain, substance abuse (especially in alcoholdependence), and spasticity.

In an alternative embodiment, certain of the compounds of the inventionhave a positive allosteric modulator activity.

These and other objects of the invention are described in the followingparagraphs. These objects should not be deemed to narrow the scope ofthe invention.

DETAILED DESCRIPTION OF THE INVENTION

Described herein are compounds of formula (I)

wherein R¹, R², R³, R⁴, L¹ and G¹ are defined above in the Summary andbelow in the Detailed Description. Further, compositions comprising suchcompounds and methods for treating conditions and disorders using suchcompounds and compositions are also described.

Compounds described herein may contain one or more variable(s) thatoccur more than one time in any substituent or in the formulae herein.Definition of a variable on each occurrence is independent of itsdefinition at another occurrence. Further, combinations of substituentsare permissible only if such combinations result in stable compounds.Stable compounds are compounds which can be isolated from a reactionmixture.

Definitions Of Terms

It is noted that, as used in this specification and the intended claims,the singular form “a,” “an,” and “the” include plural referents unlessthe context clearly dictates otherwise. Thus, for example, reference to“a compound” includes a single compound as well as one or more of thesame or different compounds, reference to “optionally a pharmaceuticallyacceptable carrier” refers to a single optional pharmaceuticallyacceptable carrier as well as one or more pharmaceutically acceptablecarriers, and the like.

Certain terms as used in the specification are intended to refer to thefollowing definitions, as detailed below.

The term “alkenyl” as used herein, means a straight or branchedhydrocarbon chain containing from 2 to 10 carbons and containing atleast one carbon-carbon double bond. Representative examples of alkenylinclude, but are not limited to, ethenyl, 2-propenyl,2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl,2-methyl-1-heptenyl, and 3-decenyl.

The term “alkenylene” means a divalent group derived from a straight orbranched chain hydrocarbon of from 2 to 10 carbon atoms containing atleast one double bond. Representative examples of alkenylene include,but are not limited to, —CH═CH—, —CH═CH₂CH₂—, and —CH═C(CH₃)CH₂—.

The term “alkoxy” as used herein means an alkyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, andhexyloxy.

The term “alkyl” as used herein, and likewise the term “alkyl” inalkylcarbonyl, alkylcarbonylamino, alkylsulfonyl and alkylsulfonylamino,means a straight or branched, saturated hydrocarbon chain containingfrom 1 to 10 carbon atoms. The term “lower alkyl” or “C₁-C₆alkyl” meansa straight or branched chain hydrocarbon containing from 1 to 6 carbonatoms. The term “C₁-C₃alkyl” means a straight or branched chainhydrocarbon containing from 1 to 3 carbon atoms. Representative examplesof alkyl include, but are not limited to, methyl, ethyl, n-propyl,iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl,isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl,2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

The term “alkylcarbonyl” as used herein means an alkyl group, as definedherein, appended to the parent molecular moiety through a carbonylgroup, as defined herein. Representative examples of alkylcarbonylinclude, but are not limited to, methylcarbonyl (acetyl), ethylcarbonyl,isopropylcarbonyl, n-propylcarbonyl, and the like.

The term “alkylcarbonylamino” as used herein means an alkylcarbonylgroup, as defined herein, appended to the parent molecular moietythrough an amino group, as defined herein. Representative examples ofalkylcarbonylamino include, but are not limited to, methylcarbonylamino,ethylcarbonylamino, isopropylcarbonylamino, n-propylcarbonylamino, andthe like.

The term “alkylsulfonyl,” as used herein, refers to an alkyl group, asdefined herein, appended to the parent molecular moiety through asulfonyl group, as defined herein. Representative examples ofalkylsulfonyl include, but are not limited to, methylsulfonyl andethylsulfonyl.

The term “alkylsulfonylamino” as used herein means an alkylsulfonylgroup, as defined herein, appended to the parent molecular moietythrough an amino group, as defined herein. Representative examples ofalkylsulfonylamino include, but are not limited to, methylsulfonylamino,ethylsulfonylamino, and the like.

The term “alkylene” denotes a divalent group derived from a straight orbranched chain hydrocarbon containing from 1 to 10 carbon atoms.Representative examples of alkylene include, but are not limited to,—CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and —CH₂CH(CH₃)CH₂—.

The term “alkynyl” as used herein, means a straight or branched chainhydrocarbon group containing from 2 to 10 carbon atoms and containing atleast one carbon-carbon triple bond. Representative examples of alkynylinclude, but are not limited to, acetylenyl, 1-propynyl, 2-propynyl,3-butynyl, 2-pentynyl, and 1-butynyl.

The term “amido” as used herein means a —C(O)NH₂ group.

The term “amino” as used herein means an —NH₂ group.

The term “aryl” as used herein, means phenyl or a bicyclic aryl. Thebicyclic aryl is naphthyl, or a phenyl fused to a monocyclic cycloalkyl,or a phenyl fused to a monocyclic cycloalkenyl. Representative examplesof the aryl groups include, but are not limited to, dihydroindenyl,indenyl, naphthyl, dihydronaphthalenyl, and tetrahydronaphthalenyl. Thebicyclic aryl is attached to the parent molecular moiety through anycarbon atom contained within the bicyclic ring system. The aryl groupsof the present invention can be unsubstituted or substituted.

The term “carbonyl” as used herein means a —C(═O)— group.

The term “carboxy” as used herein means a —CO₂H group.

The term “cyano” as used herein, means a —CN group.

The term “cycloalkenyl” or “cycloalkene” as used herein, means amonocyclic or a bicyclic hydrocarbon ring system. The monocycliccycloalkenyl has four-, five-, six-, seven- or eight carbon atoms andzero heteroatoms. The four-membered ring systems have one double bond,the five- or six-membered ring systems have one or two double bonds, andthe seven- or eight-membered ring systems have one, two or three doublebonds. Representative examples of monocyclic cycloalkenyl groupsinclude, but are not limited to, cyclobutenyl, cyclopentenyl,cyclohexenyl, cycloheptenyl and cyclooctenyl. The bicyclic cycloalkenylis a monocyclic cycloalkenyl fused to a monocyclic cycloalkyl group, ora monocyclic cycloalkenyl fused to a monocyclic cycloalkenyl group, or abridged monocyclic ring system in which two non-adjacent carbon atoms ofthe monocyclic ring are linked by an alkylene bridge containing one,two, three, or four carbon atoms. Representative examples of thebicyclic cycloalkenyl groups include, but are not limited to,4,5,6,7-tetrahydro-3aH-indene, octahydronaphthalenyl and1,6-dihydro-pentalene. The monocyclic and bicyclic cycloalkenyl can beattached to the parent molecular moiety through any substitutable atomcontained within the ring systems, and can be unsubstituted orsubstituted.

The term “cycloalkyl” or “cycloalkane” as used herein, means amonocyclic, a bicyclic, a tricyclic, or a spirocyclic cycloalkyl. Themonocyclic cycloalkyl is a carbocyclic ring system containing three toeight carbon atoms, zero heteroatoms and zero double bonds. Examples ofmonocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl. The bicyclic cycloalkyl is amonocyclic cycloalkyl fused to a monocyclic cycloalkyl ring, or abridged monocyclic ring system in which two non-adjacent carbon atoms ofthe monocyclic ring are linked by an alkylene bridge containing one,two, three, or four carbon atoms. Representative examples of bicyclicring systems include, but are not limited to, bicyclo[3.1.1]heptane,bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane,bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. Tricyclic cycloalkylsare exemplified by a bicyclic cycloalkyl fused to a monocycliccycloalkyl, or a bicyclic cycloalkyl in which two non-adjacent carbonatoms of the ring systems are linked by an alkylene bridge of 1, 2, 3,or 4 carbon atoms. Representative examples of tricyclic-ring systemsinclude, but are not limited to, tricyclo[3.3.1.0^(3,7)]nonane(octahydro-2,5-methanopentalene or noradamantane), andtricyclo[3.3.1.1^(3,7)]decane (adamantane). The monocyclic, bicyclic,and tricyclic cycloalkyls can be unsubstituted or substituted, and areattached to the parent molecular moiety through any substitutable atomcontained within the ring system. Spirocyclic cycloalkyl is exemplifiedby a monocyclic or a bicyclic cycloalkyl, wherein two of thesubstituents on the same carbon atom of the ring, together with saidcarbon atom, form a 4-, 5-, or 6-membered monocyclic cycloalkyl. Anexample of a spirocyclic cycloalkyl is spiro[2.5]octane. The spirocycliccycloalkyl groups of the present invention can be appended to the parentmolecular moiety through any substitutable carbon atom of the groups.

The term “cycloalkylalkyl” as used herein, means a cycloalkyl groupappended to the parent molecular moiety through an alkyl group, asdefined herein.

The term “halo” or “halogen” as used herein, means Cl, Br, I, or F.

The term “haloalkyl” as used herein, means an alkyl group, as definedherein, in which one, two, three, four, five, six, seven or eighthydrogen atoms are replaced by halogen. Representative examples ofhaloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl,2,2,2-trifluoroethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl,2-chloro-3-fluoropentyl, and trifluoropropyl such as3,3,3-trifluoropropyl. A subgroup of “haloalkyl” is fluoroalkyl, whichmeans an alkyl group, as defined herein, in which one, two, three, four,five, six, seven or eight hydrogen atoms are replaced by fluorine.

The term “heteroaryl” as used herein, means a heterocyclic aromaticradical and includes monocyclic heteroaryl and a bicyclic heteroaryl.The monocyclic heteroaryl is a five- or six-membered ring. Thefive-membered ring contains two double bonds. The five-membered ring maycontain one heteroatom selected from O or S; or one, two, three, or fournitrogen atoms and optionally one oxygen or sulfur atom. Thesix-membered ring contains three double bonds and one, two, three orfour nitrogen atoms. Representative examples of monocyclic heteroarylinclude, but are not limited to, furanyl, imidazolyl, isoxazolyl,isothiazolyl, oxadiazolyl, 1,3-oxazolyl, pyridinyl, pyridazinyl,pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl,1,3-thiazolyl, thienyl, triazolyl, and triazinyl. The bicyclicheteroaryl consists of a monocyclic heteroaryl fused to a phenyl, or amonocyclic heteroaryl fused to a monocyclic cycloalkyl, or a monocyclicheteroaryl fused to a monocyclic cycloalkenyl, or a monocyclicheteroaryl fused to a monocyclic heteroaryl, or a monocyclic heteroarylfused to a monocyclic heterocycle. Representative examples of bicyclicheteroaryl groups include, but are not limited to, benzofuranyl,benzothienyl, benzoxazolyl, benzimidazolyl, benzoxadiazolyl,6,7-dihydro-1,3-benzothiazolyl, imidazo[1,2-a]pyridinyl, indazolyl,indolyl, isoindolyl, isoquinolinyl, naphthyridinyl, pyridoimidazolyl,quinolinyl, thiazolo[5,4-b]pyridin-2-yl, thiazolo[5,4-d]pyrimidin-2-yl,and 5,6,7,8-tetrahydroquinolin-5-yl. The monocyclic and bicyclicheteroaryl groups of the present invention can be substituted orunsubstituted and are connected to the parent molecular moiety throughany carbon atom or any nitrogen atom contained within the ring systems.

The term “heterocycle” or “heterocyclic” as used herein, means anon-aromatic heterocyclic radical and includes a monocyclic heterocycle,a bicyclic heterocycle, a tricyclic heterocycle, or a spirocyclicheterocycle. If not stated otherwise, the heterocyclic radical issaturated or has one or two non-conjugated endocyclic double bounds,e.g. a C═N or C═C double bond. The monocyclic heterocycle is a three-,four-, five-, six-, seven-, or eight-membered ring containing at leastone heteroatom independently selected from the group consisting of O, N,and S. The three- or four-membered ring contains zero or one doublebond, and one heteroatom selected from the group consisting of O, N, andS. The five-membered ring contains zero or one double bond and one, twoor three heteroatoms selected from the group consisting of O, N and S.The six-membered ring contains zero, one or two double bonds and one,two, or three heteroatoms selected from the group consisting of O, N,and S. The seven- and eight-membered rings contains zero, one, two, orthree double bonds and one, two, or three heteroatoms selected from thegroup consisting of O, N, and S. Representative examples of monocyclicheterocycles include, but are not limited to, azetidinyl, azepanyl,aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl,1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl,isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl,oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl,piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl,pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydropyridinyl, tetrahydrothienyl, thiadiazolinyl,thiadiazolidinyl, 1,2-thiazinanyl, 1,3-thiazinanyl, thiazolinyl,thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl(thiomorpholine sulfone), thiopyranyl, and trithianyl. The bicyclicheterocycle is a monocyclic heterocycle fused to a phenyl group, or amonocyclic heterocycle fused to a monocyclic cycloalkyl, or a monocyclicheterocycle fused to a monocyclic cycloalkenyl, or a monocyclicheterocycle fused to a monocyclic heterocycle, or a bridged monocyclicheterocycle ring system in which two non-adjacent atoms of the ring arelinked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or analkenylene bridge of two, three, or four carbon atoms. Representativeexamples of bicyclic heterocycles include, but are not limited to,benzopyranyl, benzothiopyranyl, chromanyl, 2,3-dihydrobenzofuranyl,2,3-dihydrobenzothienyl, 2,3-dihydroisoquinoline,azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]hept-2-yl),2,3-dihydro-1H-indolyl, isoindolinyl, octahydrocyclopenta[c]pyrrolyl,octahydropyrrolopyridinyl, and tetrahydroisoquinolinyl. Tricyclicheterocycles are exemplified by a bicyclic heterocycle fused to a phenylgroup, or a bicyclic heterocycle fused to a monocyclic cycloalkyl, or abicyclic heterocycle fused to a monocyclic cycloalkenyl, or a bicyclicheterocycle fused to a monocyclic heterocycle, or a bicyclic heterocyclein which two non-adjacent atoms of the bicyclic ring are linked by analkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridgeof two, three, or four carbon atoms. Examples of tricyclic heterocyclesinclude, but not limited to, octahydro-2,5-epoxypentalene,hexahydro-2H-2,5-methanocyclopenta[b]furan,hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-adamantane(1-azatricyclo[3.3.1.1^(3,7)]decane), oxa-adamantane(2-oxatricyclo[3.3.1.1^(3,7)]decane), andoctahydro-1H-4,7-epiminoisoindole. The spirocyclic heterocycles areexemplified by a monocyclic heterocycle as defined herein wherein onecarbon atom of the monocyclic heterocycle is bridged by two ends of analkylene chain. In the spirocyclic heterocycle, one or more carbon atomsin the bridging alkylene chain may be replaced with a heteroatom.Examples of spirocyclic heterocycles include, but are not limited to,4,7-diazaspiro[2.5]octane, 2-oxa-6-azaspiro[3.3]heptane,2,6-diazaspiro[3.3]heptane, 2-oxa-5,8-diazaspiro[3.5]nonane,2,7-diazaspiro[3.5]nonane, 1,4-dioxa-8-azaspiro[4.5]decane,1,6-diazaspiro[3.3]heptane, 1-azaspiro[4.4]nonane,7-azaspiro[3.5]nonane, 1,4-dioxa-7-azaspiro[4.4]nonane,5,8-diazaspiro[3.5]nonane, 5,8-dioxa-2-azaspiro[3.4]octane,2-oxa-6-azaspiro[3.4]octane, 6-oxa-1-azaspiro[3.3]heptane,6-oxa-2-azaspiro[3.4]octane, 6-oxa-2-azaspiro[3.5]nonane, and7-oxa-2-azaspiro[3.5]nonane. The monocyclic, bicyclic, tricyclic, andspirocyclic heterocycles are connected to the parent molecular moietythrough any carbon atom or any nitrogen atom contained within the rings,and can be unsubstituted or substituted.

The term “heterocyclealkyl”, as used herein, refers to refers to aheterocycle group attached to the parent molecular moiety through analkyl group.

The term “heteroatom” as used herein, means a nitrogen, oxygen, orsulfur atom.

The term “hydroxyl” or “hydroxy” as used herein, means an —OH group.

The term “hydroxyalkyl” as used herein, means at least one hydroxygroup, as defined herein, is appended to the parent molecular moietythrough an alkylene group, as defined herein. Representative examples ofhydroxyalkyl include, but are not limited to, hydroxymethyl,2-hydroxyethyl, 3-hydroxypropyl, and 2-ethyl-4-hydroxyheptyl.

The term “oxo” as used herein means (═O).

The term “sulfonyl,” as used herein, refers to a —S(O)₂— group.

In some instances, the number of carbon atoms in a hydrocarbylsubstituent (e.g., alkyl, haloalkyl, alkenyl, alkynyl, alkylene, alkoxy,haloalkoxy or cycloalkyl) is indicated by the prefix “C_(x)-C_(y)”,wherein x is the minimum and y is the maximum number of carbon atoms inthe substituent. Thus, for example, “C₁-C₆alkyl” refers to an alkylsubstituent containing from 1 to 6 carbon atoms. Illustrating further,C₃-C₆cycloalkyl means a saturated hydrocarbyl ring containing from 3 to6 carbon ring atoms.

As used herein, the term “radiolabel” refers to a compound of theinvention in which at least one of the atoms is a radioactive atom orradioactive isotope, wherein the radioactive atom or isotopespontaneously emits gamma rays or energetic particles, for example alphaparticles or beta particles, or positrons. Examples of such radioactiveatoms include, but are not limited to, ³H (tritium), ¹⁴C, ¹¹C, ¹⁵O, ¹⁸F,³⁵S, ¹²³I, and ¹²⁵I.

If a moiety is described as “substituted”, a non-hydrogen radical is inthe place of hydrogen radical of any substitutable atom of the moiety.Thus, for example, a substituted heterocycle moiety is a heterocyclemoiety in which at least one non-hydrogen radical is in the place of ahydrogen radical on the heterocycle. It should be recognized that ifthere are more than one substitution on a moiety, each non-hydrogenradical may be identical or different (unless otherwise stated).

If a moiety is described as being “optionally substituted,” the moietymay be either (1) not substituted or (2) substituted. If a moiety isdescribed as being optionally substituted with up to a particular numberof non-hydrogen radicals, that moiety may be either (1) not substituted;or (2) substituted by up to that particular number of non-hydrogenradicals or by up to the maximum number of substitutable positions onthe moiety, whichever is less. Thus, for example, if a moiety isdescribed as a heteroaryl optionally substituted with up to 3non-hydrogen radicals, then any heteroaryl with less than 3substitutable positions would be optionally substituted by up to only asmany non-hydrogen radicals as the heteroaryl has substitutablepositions. To illustrate, tetrazolyl (which has only one substitutableposition) would be optionally substituted with up to one non-hydrogenradical. To illustrate further, if an amino nitrogen is described asbeing optionally substituted with up to 2 non-hydrogen radicals, then aprimary amino nitrogen will be optionally substituted with up to 2non-hydrogen radicals, whereas a secondary amino nitrogen will beoptionally substituted with up to only 1 non-hydrogen radical.

The terms “treat”, “treating”, and “treatment” refer to a method ofalleviating or abrogating a disease and/or its attendant symptoms.

The terms “prevent”, “preventing”, and “prevention” refer to a method ofpreventing the onset of a disease and/or its attendant symptoms orbarring a subject from acquiring a disease. As used herein, “prevent”,“preventing” and “prevention” also include delaying the onset of adisease and/or its attendant symptoms and reducing a subject's risk ofacquiring a disease.

The phrase “therapeutically effective amount” means an amount of acompound, or a pharmaceutically acceptable salt thereof, sufficient toprevent the development of or to alleviate to some extent one or more ofthe symptoms of the condition or disorder being treated whenadministered alone or in conjunction with another therapeutic agent ortreatment in a particular subject or subject population. For example ina human or other mammal, a therapeutically effective amount can bedetermined experimentally in a laboratory or clinical setting, or may bethe amount required by the guidelines of the United States Food and DrugAdministration, or equivalent foreign agency, for the particular diseaseand subject being treated.

The term “subject” is defined herein to refer to animals such asmammals, including, but not limited to, primates (e.g., humans), cows,sheep, goats, pigs, horses, dogs, cats, rabbits, rats, mice and thelike. In preferred embodiments, the subject is a human.

Compounds of the Invention

Compounds of the invention can have the formula (I) as described in theSummary.

Particular values of variable groups in compounds of formula (I) are asfollows. Such values can be used where appropriate with any of the othervalues, definitions, claims or embodiments defined hereinbefore orhereinafter.

Irrespectively of its occurrence, R¹ is as defined above or selectedfrom the group consisting of C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₃-C₆cycloalkyl, C₃-C₆cycloalkylC₁-C₆alkyl, 4-7-membered heterocycle and4-7-membered heterocycleC₁-C₆alkyl; where

-   -   a) the C₁-C₆alkyl, the C₂-C₆alkenyl, the C₂-C₆alkynyl, the        C₁-C₆alkyl of C₃-C₆cycloalkylC₁-C₆alkyl, and the C₁-C₆alkyl of        4-7-membered heterocycleC₁-C₆alkyl are unsubstituted or        substituted with one or more, e.g. 1, 2, 3, 4 or 5 substituents        R^(1a);    -   b) the C₃-C₆cycloalkyl, the C₃-C₆cycloalkyl of        C₃-C₆cycloalkylC₁-C₆alkyl, 4-7-membered heterocycle, and the        4-7-membered heterocycle of 4-7-membered heterocycleC₁-C₆alkyl        are unsubstituted or substituted with one or more, e.g. 1, 2, 3        or 4, substituents R^(1b).

Irrespectively of its occurrence, R¹ is more particularly selected fromthe group consisting of

-   -   C₁-C₆alkyl, which is unsubstituted or substituted by 1, 2, 3 or        4 radicals R^(1a),    -   C₃-C₆cycloalkyl and C₃-C₆cycloalkylC₁-C₆alkyl; where        C₃-C₆cycloalkyl and the C₃-C₆cycloalkyl of        C₃-C₆cycloalkylC₁-C₆alkyl, are unsubstituted or substituted with        one or more, e.g. 1, 2, 3 or 4, substituents R^(1b).

In this context, R^(1a) is in particular selected from the group ofhalogen, in particular fluorine, CN, C₁-C₄alkoxy and hydroxyl.Especially R^(1a) is fluorine.

In this context, R^(1b) is in particular selected from the group ofhalogen, in particular fluorine, C₁-C₄alkyl, CN, haloC₁-C₄alkyl,hydroxyC₁-C₄alkyl, C₁-C₄alkoxy, hydroxyl and oxo. More particularlyR^(1b) is selected from the group of fluorine, C₁-C₂alkyl,fluoroC₁-C₂alkyl, and hydroxyl. Especially R^(1b) is fluorine, methyl,or trifluoromethyl.

Irrespectively of its occurrence, R² is in particular selected from thegroup consisting of hydrogen, C₁-C₆alkyl, and haloC₁-C₆alkyl.

A particular group (1) of embodiments relates to compounds of theformula (I) and to their pharmaceutically acceptable salts, wherein R¹is selected from the group consisting of C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₃-C₆cycloalkyl, C₃-C₆cycloalkylC₁-C₆alkyl, 4-7-memberedheterocycle and 4-7-membered heterocycleC₁-C₆alkyl;

-   -   a) the C₁-C₆alkyl, the C₂-C₆alkenyl, the C₂-C₆alkynyl, the        C₁-C₆alkyl of C₃-C₆cycloalkylC₁-C₆alkyl, and the C₁-C₆alkyl of        4-7-membered heterocycleC₁-C₆alkyl are unsubstituted or        substituted with one or more substituents R^(1a);    -   b) the C₃-C₆cycloalkyl, the C₃-C₆cycloalkyl of        C₃-C₆cycloalkylC₁-C₆alkyl, 4-7-membered heterocycle, and the        4-7-membered heterocycle of 4-7-membered heterocycleC₁-C₆alkyl        are unsubstituted or substituted with one or more substituents        R^(1b); and

R² is selected from the group consisting of hydrogen, C₁-C₆alkyl, andhaloC₁-C₆alkyl and wherein R² is in particular selected from the groupconsisting hydrogen, C₁-C₄alkyl and fluoroC₁-C₄alkyl. In group (1) ofembodiments, R² is especially hydrogen.

In this group (1) of embodiments, R¹ may be in particular selected fromthe group consisting of C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, whereinthe C₁-C₆alkyl, the C₂-C₆alkenyl and the C₂-C₆alkynyl are unsubstitutedor substituted with one or more, e.g. 1, 2 or 3 halogen atoms,especially fluorine atoms. This group of embodiments is also termedgroup (1a) of embodiments. In this group (1a) of embodiments, R¹ isespecially C₁-C₆alkyl, which is unsubstituted or substituted with one ormore, e.g. 1, 2 or 3 halogen atoms, especially fluorine atoms.

In this group (1) of embodiments, R¹ may also be selected from the groupconsisting of C₃-C₆cycloalkyl, C₃-C₆cycloalkylC₁-C₆alkyl, 4-7-memberedheterocycle and 4-7-membered heterocycleC₁-C₆alkyl, especially from thegroup consisting of C₃-C₆cycloalkyl and C₃-C₆cycloalkylC₁-C₆alkyl, where

-   -   a) the C₁-C₆alkyl of C₃-C₆cycloalkylC₁-C₆alkyl, and the        C₁-C₆alkyl of 4-7-membered heterocycleC₁-C₆alkyl are        unsubstituted or substituted with one or more, e.g. 1, 2, 3, 4        or 5 substituents R^(1a); and    -   b) the C₃-C₆cycloalkyl, the C₃-C₆cycloalkyl of        C₃-C₆cycloalkylC₁-C₆alkyl, the 4-7-membered heterocycle, and the        4-7-membered heterocycle of 4-7-membered heterocycleC₁-C₆alkyl        are unsubstituted or substituted with one or more, e.g. 1, 2, 3        or 4, substituents R^(1b).

This group of embodiments is also termed group (1b) of embodiments. Inthis group (1b) of embodiments, R1 is especially C3-C6cycloalkyl orC3-C6cycloalkylC1-C6alkyl, where the C3-C6cycloalkyl or theC3-C6cycloalkyl of C3-C6cycloalkylC1-C6alkyl are unsubstituted orsubstituted with one or more, e.g. 1, 2, 3 or 4, substituents R1b.

In groups (1a) and (1b) of embodiments, R² is as defined above andespecially hydrogen.

In the context of groups (1), (1a) and (1b) of embodiments, R^(1a) is asdefined above or selected from the group of halogen, in particularfluorine, CN, C₁-C₄alkoxy and hydroxyl. Especially R^(1a) is fluorine.

In the context of groups (1), (1a) and (1b) of embodiments, R^(1b) is asdefined above or selected from the group of halogen, in particularfluorine, C₁-C₄alkyl, CN, haloC₁-C₄alkyl, hydroxyC₁-C₄alkyl,C₁-C₄alkoxy, hydroxyl and oxo. In particular, R^(1b) is selected fromthe group of fluorine, C₁-C₂alkyl, fluoroC₁-C₂alkyl, and hydroxyl.Especially R^(1b) is fluorine, methyl, or trifluoromethyl.

Particular examples of the group NR¹R² of this group (1) of embodimentsinclude 2,2,2-trifluoroethylamino, ter t-butylamino,1-(trifluoromethyl)ethylamino, 1-methylcyclopropylamino,1-(trifluoromethyl)cyclopropylamino, 3-fluorocyclobutylamino,3,3-difluorocyclobutylamino, 3-hydroxycyclobutylamino, and(3,3-difluorocyclobutyl)methylamino.

Another particular group (2) of embodiments relates to compounds of theformula (I) and to their pharmaceutically acceptable salts, wherein themoiety NR¹R² forms a saturated 4-7-membered N-bound heterocycle, whichin addition to the nitrogen atom may have one further heteroatomselected from O, S and N as a ring member, wherein each such4-7-membered heterocycle is unsubstituted or substituted with one ormore, e.g. 1, 2, 3, 4, 5 or 6, identical or different substituentsR^(1c). In this group (2) of embodiments the moiety NR¹R² is inparticular selected from the group consisting of azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl,and azepanyl wherein azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, thiomorpholinyl, and azepanyl are unsubstituted or carry 1,2, 3 or 4 identical or different radicals R^(1c).

In a subgroup (2a) of this group (2) of embodiments the moiety NR¹R² isa 4-5-membered heterocycle selected from the group consisting ofazetidinyl and pyrrolidinyl, wherein azetidinyl and pyrrolidinyl areunsubstituted or carry 1, 2, 3 or 4 identical or different radicalsR^(1c).

In another subgroup (2b) of this group (2) of embodiments the moietyNR¹R² is a 6-7-membered heterocycle selected from the group consistingof piperidinyl, piperazinyl and azepanyl wherein piperidinyl,piperazinyl and azepanyl are unsubstituted or carry 1, 2, 3 or 4identical or different radicals R^(1c).

In the context of groups (2), (2a) and (2b) of embodiments, R^(1c) is asdefined above or selected from the group consisting of halogen, inparticular fluorine, oxo, hydroxyl, C₁-C₆alkyl, such as methyl or ethyl,haloC₁-C₆alkyl, in particular fluoroC₁-C₂alkyl, such as difluoromethyl,trifluoromethyl or 2,2,2-trifluoroethyl, hydroxC₁-C₆yalkyl, such ashydroxymethyl or 2-hydroxyethyl, C₁-C₆alkylcarbonylamino, such asmethylcarbonylamino, C₁-C₆alkylsulfonylamino, such asmethylsulfonylamino, amido, carboxy, spiro-bound saturatedC₃-C₆cycloalkyl, and spiro-bound saturated 4-6-membered heterocycle,where the spiro-bound C₃-C₆cycloalkyl and the spiro-bound 4-6-memberedheterocycle are unsubstituted or carry 1 or 2 radicals as defined above,which are in particular selected from halogen, hydroxyl, C₁-C₂alkyl andfluoroC₁-C₂alkyl. Examples of spiro-bound radicals include spiro-boundcyclopropyl, spiro-bound cyclobutyl, spiro-bound cyclopentyl,spiro-bound hydroxycyclopropyl, spiro-bound hydroxycyclobutyl,spiro-bound hydroxycyclopentyl, spiro bound oxetanyl, spiro-boundoxolanyl and spiro-bound oxanyl.

In the context of groups (2), (2a) and (2b) of embodiments, R^(1c) isespecially selected from the group consisting of halogen, in particularfluorine, hydroxyl, methyl, ethyl, hydroxymethyl, 2-hydroxyethyl,methylcarbonylamino, methylsulfonylamino, amido, carboxy, spiro-boundcyclopropyl, spiro-bound cyclobutyl, spiro-bound cyclopentyl,spiro-bound hydroxycyclopropyl, spiro-bound hydroxycyclobutyl,spiro-bound hydroxycyclopentyl, spiro bound oxetanyl, spiro-boundoxolanyl and spiro-bound oxanyl.

Particular examples of the group NR¹R² in this group (2) of embodimentsinclude azetidin-1-yl, 3-ethyl-2-carboxylazetidin-1-yl, pyrroldin-1-yl,3,3-difluoropyrrolidin-1-yl, 3-(acetyl amino)pyrrolidin-1-yl,3-(methylsulfonylamino)pyrrolidin-1-yl, 3-aminocarbonylpyrrolidin-1-yl,piperidin-1-yl, 3-fluoropiperidin-1-yl, 4-fluoropiperidin-1-yl,2-(2-hydroxyethyl)piperidin-1-yl, 2-ethylpiperidin-1-yl,2-(hydroxymethyl)piperidin-1-yl, 3-(hydroxymethyl)piperidin-1-yl,2-oxopiperidin-1-yl, 3-(methylsulfonylamino)piperidin-1-yl,2-(2-hydroxyethyl)-3-oxopiperazin-1-yl, 3-difluorpiperidin-1-yl,3-hydroxypiperidin-1-yl, 4-hydroxy-3,3-difluoropiperidin-1-yl,2-oxa-6-azaspiro[3.4]oct-6-yl, 2-oxa-7-azaspiro-[3.5]non-7-yl,7-oxa-2-azaspiro[3.5]non-2-yl and 3-hydroxy-7-azaspiro[3.4]oct-7-yl.

A particular group (A) of embodiments relates to compounds of theformula (I) and to their pharmaceutically acceptable salts, wherein L¹is —(CR⁵R⁶)_(m)—, wherein m, R⁵ and R⁶ are as defined herein. Inparticular m is 1. In particular R⁵ and R⁶ are, independently selectedfrom the group consisting of hydrogen and C₁-C₆alkyl, especially fromhydrogen and C₁-C₄-alkyl, such as methyl, ethyl, n-propyl, 2-propyl andn-butyl. Especially, both R⁵ and R⁶ are hydrogen or R⁵ is hydrogen andR⁶ is C₁-C₆alkyl.

Another group (B) of embodiments relates to compounds of the formula (I)and to their pharmaceutically acceptable salts, wherein L¹ is—(CH₂)₆CR^(5a)═CR^(6a)(CH₂)_(p)—. In this group (2) of embodiments, nand p are in particular 0. In particular, R^(5a) and R^(6a) are,independently selected from the group consisting of hydrogen andC₁-C₆alkyl, especially from the group consisting of hydrogen and methyl.

Another group (C) of embodiments relates to compounds of the formula (I)and to their pharmaceutically acceptable salts, wherein L¹ is

In this particular group (3) of embodiments, n and p are as definedabove or in particular 0. R^(5b) and R^(6b) are as defined above orindependently selected from the group consisting of hydrogen andC₁-C₆alkyl. Especially, R^(5b) and R^(6b) are hydrogen or methyl.

Further particular groups of embodiments relate to compounds of theformula (I) and to their pharmaceutically acceptable salts, inparticular to the compounds of groups (1), (1a), (1b), (2), (2a), (2b),(A), (B) and (C) of embodiments, wherein G¹ is selected from the groupconsisting of 5-6-membered heteroaryl and phenyl, wherein the5-6-membered heteroaryl and phenyl are unsubstituted or carry 1, 2, 3 or4 radicals R^(G). In particular G¹ is selected from the group consistingof 6-membered heteroaryl, such as pyridyl, pyrimidinyl, pyrazinyl orpyridazinyl, and phenyl, wherein the 6-membered heteroaryl and phenylare unsubstituted or carry 1, 2, 3 or 4 radicals R^(G). Moreparticularly, G¹ is selected from the group consisting of pyridyl, suchas 2- or 3-pyridyl, and phenyl, wherein the pyridyl and phenyl areunsubstituted or carry 1, 2 or 3 radicals R^(G). Especially, G¹ isphenyl, which is unsubstituted or carries 1, 2 or 3 radicals R^(G).

In this context R^(G) is as defined above or selected from the groupconsisting of C₁-C₆alkyl, haloC₁-C₆alkyl, and halogen, in particularfrom the group consisting of C₁-C₄alkyl, fluoroC₁-C₄alkyl, fluorine andchlorine, and especially from the group consisting of fluoroC₁-C₂alkyl,fluorine and chlorine.

Particular examples of G¹ include but are not limited to phenyl,3-chlorophenyl, 4-chlorophenyl, 4-(trifluoromethyl)phenyl, pyridine-2-yland 5-chloropyridin-2-yl.

In formula (I) and likewise in the compounds of groups (1), (1a), (1b),(2), (2a), (2b), (A), (B) and (C) of embodiments, R³ is as defined aboveor in particular hydrogen.

In formula (I) and likewise in the compounds of groups (1), (1a), (1b),(2), (2a), (2b), (A), (B) and (C) of embodiments, R⁴ is as defined aboveor C₁-C₆alkyl, in particular C₁-C₄alkyl, and especially methyl or ethyl.

In particular, the present invention relates to compounds of the formula(I) and to their pharmaceutically acceptable salts, wherein thecombination variables L¹, G¹, R³ and R⁴ are as follows:

L¹ is —(CR⁵R⁶)_(m)—, wherein m is 1 and wherein R⁵ and R⁶ are,independently selected from the group consisting of hydrogen andC₁-C₆alkyl, especially from hydrogen and C₁-C₄-alkyl, such as methyl,ethyl, n-propyl, 2-propyl and n-butyl. More particularly, both R⁵ and R⁶are hydrogen or R⁵ is hydrogen and R⁶ is C₁-C₄alkyl;

G¹ is selected from the group consisting of 5-6-membered heteroaryl andphenyl, wherein the 5-6-membered heteroaryl and phenyl are unsubstitutedor carry 1, 2, 3 or 4 radicals R^(G). In particular G¹ is selected fromthe group consisting of 6-membered heteroaryl, such as pyridyl,pyrimidinyl, pyrazinyl or pyridazinyl, and phenyl, wherein the6-membered heteroaryl and phenyl are unsubstituted or carry 1, 2, 3 or 4radicals R^(G). More particularly, G¹ is selected from the groupconsisting of pyridyl, such as 2- or 3-pyridyl, and phenyl, wherein thepyridyl and phenyl are unsubstituted or carry 1, 2 or 3 radicals R^(G).Especially, G¹ is phenyl, which is unsubstituted or carries 1, 2 or 3radicals R^(G). In this context R^(G) is in particular selected from thegroup consisting of C₁-C₆alkyl, haloC₁-C₆alkyl, and halogen, inparticular from the group consisting of C₁-C₄alkyl, fluoroC₁-C₄alkyl,fluorine and chlorine, and especially from the group consisting offluoroC₁-C₂alkyl, fluorine and chlorine;

R³ is hydrogen; and

R⁴ is C₁-C₄alkyl, and especially methyl or ethyl.

More particularly, the present invention relates to compounds of theformula (I) and to their pharmaceutically acceptable salts, wherein thecombination variables L¹, G¹, R³ and R⁴ are as follows:

L¹ is —(CR⁵R⁶)_(m)—, wherein m is 1 and wherein R⁵ and R⁶ are,independently selected from the group consisting of hydrogen andC₁-C₆alkyl, especially from hydrogen and C₁-C₄-alkyl, such as methyl,ethyl, n-propyl, 2-propyl and n-butyl. More particularly, both R⁵ and R⁶are hydrogen or R⁵ is hydrogen and R⁶ is C₁-C₄alkyl;

G¹ is selected from the group consisting of phenyl, 3-chlorophenyl,4-chlorophenyl, 4-(trifluoromethyl)phenyl, pyridine-2-yl and5-chloropyridin-2-yl;

R³ is hydrogen; and

R⁴ is C₁-C₄alkyl, and especially methyl or ethyl.

More particularly, the present invention also relates to compounds ofthe formula (I) and to their pharmaceutically acceptable salts, whereinthe combination variables L¹, G¹, R¹, R², R³ and R⁴ are as follows:

L¹ is —(CR⁵R⁶)_(m)—, wherein m is 1 and wherein R⁵ and R⁶ are,independently selected from the group consisting of hydrogen andC₁-C₆alkyl, especially from hydrogen and C₁-C₄-alkyl, such as methyl,ethyl, n-propyl, 2-propyl and n-butyl. More particularly, both R⁵ and R⁶are hydrogen and especially R⁵ is hydrogen and R⁶ is C₁-C₄alkyl;

G¹ is selected from the group consisting of 5-6-membered heteroaryl andphenyl, wherein the 5-6-membered heteroaryl and phenyl are unsubstitutedor carry 1, 2, 3 or 4 radicals R^(G). In particular G¹ is selected fromthe group consisting of 6-membered heteroaryl, such as pyridyl,pyrimidinyl, pyrazinyl or pyridazinyl, and phenyl, wherein the6-membered heteroaryl and phenyl are unsubstituted or carry 1, 2, 3 or 4radicals R^(G). More particularly, G¹ is selected from the groupconsisting of pyridyl, such as 2- or 3-pyridyl, and phenyl, wherein thepyridyl and phenyl are unsubstituted or carry 1, 2 or 3 radicals R^(G).Especially, G¹ is s phenyl, which is unsubstituted or carries 1, 2 or 3radicals R^(G). In this context R^(G) is as defined above or selectedfrom the group consisting of C₁-C₆alkyl, haloC₁-C₆alkyl, and halogen, inparticular from the group consisting of C₁-C₄alkyl, fluoroC₁-C₄alkyl,fluorine and chlorine, and especially from the group consisting offluoro C₁-C₂alkyl, fluorine and chlorine;

R³ is hydrogen;

R⁴ is C₁-C₄alkyl, and especially methyl or ethyl;

and R¹ and R² are as defined for groups (1), (1a) or (1b) ofembodiments.

More particularly, the present invention also relates to compounds ofthe formula (I) and to their pharmaceutically acceptable salts, whereinthe combination variables L¹, G¹, NR¹R², R³ and R⁴ are as follows:

L¹ is —(CR⁵R⁶)_(m)—, wherein m is 1 and wherein R⁵ and R⁶ are,independently selected from the group consisting of hydrogen andC₁-C₆alkyl, especially from hydrogen and C₁-C₄-alkyl, such as methyl,ethyl, n-propyl, 2-propyl and n-butyl. More particularly, both R⁵ and R⁶are hydrogen or R⁵ is hydrogen and R⁶ is C₁-C₄alkyl;

G¹ is selected from the group consisting of 5-6-membered heteroaryl andphenyl, wherein the 5-6-membered heteroaryl and phenyl are unsubstitutedor carry 1, 2, 3 or 4 radicals R^(G). In particular G¹ is selected fromthe group consisting of 6-membered heteroaryl, such as pyridyl,pyrimidinyl, pyrazinyl or pyridazinyl, and phenyl, wherein the6-membered heteroaryl and phenyl are unsubstituted or carry 1, 2, 3 or 4radicals R^(G). More particularly, G¹ is selected from the groupconsisting of pyridyl, such as 2- or 3-pyridyl, and phenyl, wherein thepyridyl and phenyl are unsubstituted or carry 1, 2 or 3 radicals R^(G).Especially, G¹ is s phenyl, which is unsubstituted or carries 1, 2 or 3radicals R^(G). In this context R^(G) is in particular selected from thegroup consisting of C₁-C₆alkyl, haloC₁-C₆alkyl, and halogen, inparticular from the group consisting of C₁-C₄alkyl, fluoroC₁-C₄alkyl,fluorine and chlorine, and especially from the group consisting offluoroC₁-C₂alkyl, fluorine and chlorine;

R³ is hydrogen;

R⁴ is C₁-C₄alkyl, and especially methyl or ethyl;

and NR¹R² is as defined for groups (2), (2a) or (2b) of embodiments.

Especially, the present invention relates to compounds of the formula(I) and to their pharmaceutically acceptable salts, wherein thecombination variables L¹, G¹, R¹, R², R³ and R⁴ are as follows:

L¹ is —(CR⁵R⁶)_(m)—, wherein m is 1 and wherein R⁵ and R⁶ are,independently selected from the group consisting of hydrogen andC₁-C₆alkyl, especially from hydrogen and C₁-C₄-alkyl, such as methyl,ethyl, n-propyl, 2-propyl and n-butyl. More particularly, both R⁵ and R⁶are hydrogen or R⁵ is hydrogen and R⁶ is C₁-C₄alkyl;

G¹ is selected from the group consisting of phenyl, 3-chlorophenyl,4-chlorophenyl, 4-(trifluoromethyl)phenyl, pyridine-2-yl and5-chloropyridin-2-yl;

R³ is hydrogen;

R⁴ is C₁-C₄alkyl, and especially methyl or ethyl;

and R¹ and R² are as defined for groups (1), (1a) or (1b) of embodimentsand wherein the moiety NR¹R² is in particular selected from the groupconsisting of 2,2,2-trifluoroethylamino, tert-butylamino,1-(trifluoromethyl)ethylamino, 1-methylcyclopropylamino,1-(trifluoromethyl)cyclopropylamino, 3-fluorocyclobutylamino,3,3-difluorocyclobutylamino, 3-hydroxycyclobutylamino, and(3,3-difluorocyclobutyl)methylamino.

Especially, the present invention relates to compounds of the formula(I) and to their pharmaceutically acceptable salts, wherein thecombination variables L¹, G¹, NR¹R², R³ and R⁴ are as follows:

L¹ is —(CR⁵R⁶)_(m)—, wherein m is 1 and wherein R⁵ and R⁶ are,independently selected from the group consisting of hydrogen andC₁-C₆alkyl, especially from hydrogen and C₁-C₄-alkyl, such as methyl,ethyl, n-propyl, 2-propyl and n-butyl. More particularly, both R⁵ and R⁶are hydrogen or R⁵ is hydrogen and R⁶ is C₁-C₄alkyl;

G¹ is selected from the group consisting of phenyl, 3-chlorophenyl,4-chlorophenyl, 4-(trifluoromethyl)phenyl, pyridine-2-yl and5-chloropyridin-2-yl;

R³ is hydrogen;

R⁴ is C₁-C₄alkyl, and especially methyl or ethyl;

and NR¹R² is as defined for groups (2), (2a) or (2b) of embodiments, andwherein the moiety NR¹R² is in particular selected from the groupconsisting of azetidin-1-yl, 3-ethyl-2-carboxylazetidin-1-yl,pyrroldin-1-yl, 3,3-difluoropyrrolidin-1-yl,3-(acetylamino)pyrrolidin-1-yl, 3-(methylsulfonylamino)pyrrolidin-1-yl,3-aminocarbonylpyrrolidin-1-yl, piperidin-1-yl, 3-fluoropiperidin-1-yl,4-fluoropiperidin-1-yl, 2-(2-hydroxyethyl)piperidin-1-yl,2-ethylpiperidin-1-yl, 2-(hydroxymethyl)piperidin-1-yl,3-(hydroxymethyl)piperidin-1-yl, 2-oxopiperidin-1-yl,3-(methylsulfonylamino)piperidin-1-yl,2-(2-hydroxyethyl)-3-oxopiperazin-1-yl, 3,3-difluorpiperidin-1-yl,3-hydroxypiperidin-1-yl, 4-hydroxy-3,3-difluoropiperidin-1-yl,2-oxa-6-azaspiro[3.4]oct-6-yl, 2-oxa-7-azaspiro-[3.5]non-7-yl,7-oxa-2-azaspiro[3.5]non-2-yl and 3-hydroxy-7-azaspiro[3.4]oct-7-yl.

Specific embodiments contemplated as part of the invention also include,but are not limited to, compounds or pharmaceutically acceptable saltsthereof, as defined, for example:

-   2-{1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidin-2-yl}ethanol;-   {1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidin-2-yl}methanol;-   2-(4-chlorobenzyl)-5-methyl-N-(1-methylcyclopropyl)pyrazolo[1,5-a]pyrimidin-7-amine;-   2-(4-chlorobenzyl)-7-(3,3-difluoropiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine;-   1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]-3,3-difluoropiperidin-4-ol;-   (3S)-1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidin-3-ol;-   (3R)-1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidin-3-ol;-   {(3S)-1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidin-3-yl}methanol;-   2-(4-chlorobenzyl)-5-methyl-7-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidine;-   1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidin-2-one;-   N-{(3R)-1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]pyrrolidin-3-yl}acetamide;-   2-(4-chlorobenzyl)-5-methyl-7-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine;-   7-(azetidin-1-yl)-2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidine;-   N-tert-butyl-2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-amine;-   2-(4-chlorobenzyl)-5-methyl-N-[1-(trifluoromethyl)cyclopropyl]pyrazolo[1,5-a]pyrimidin-7-amine;-   2-(4-chlorobenzyl)-5-methyl-N-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyrimidin-7-amine;-   N-{(3S)-1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]pyrrolidin-3-yl}acetamide;-   2-(4-chlorobenzyl)-5-methyl-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyrazolo[1,5-a]pyrimidin-7-amine;-   1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidine-3-carboxamide;-   2-(4-chlorobenzyl)-5-methyl-N-[(2R)-1,1,1-trifluoropropan-2-yl]pyrazolo[1,5-a]pyrimidin-7-amine;-   {(3R)-1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidin-3-yl}methanol;-   2-(1-{2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}piperidin-2-yl)ethanol;-   2-[1-(4-chlorophenyl)ethyl]-5-methyl-N-(1-methylcyclopropyl)pyrazolo[1,5-a]pyrimidin-7-amine;-   2-[1-(4-chlorophenyl)ethyl]-7-(3,3-difluoropyrrolidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine;-   2-[1-(4-chlorophenyl)ethyl]-7-(4-fluoropiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine;-   (1-{2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}piperidin-2-yl)methanol;-   2-[1-(4-chlorophenyl)ethyl]-7-(3-fluoropiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine;-   2-[1-(4-chlorophenyl)ethyl]-7-(3,3-difluoropiperidin-1-yl)-5-methylpyrazol[1,5-a]pyrimidine;-   N-tert-butyl-2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazol[1,5-a]pyrimidin-7-amine;-   2-[1-(4-chlorophenyl)ethyl]-5-methyl-7-(2-oxa-7-azaspiro[3.5]non-7-yl)pyrazolo[1,5-a]pyrimidine;-   (3S)-1-{2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}piperidin-3-ol;-   (3R)-1-{2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}piperidin-3-ol;-   7-(azetidin-1-yl)-2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidine;-   2-[1-(4-chlorophenyl)ethyl]-5-methyl-7-(7-oxa-2-azaspiro[3.5]non-2-yl)pyrazolo[1,5-a]pyrimidine;-   2-[1-(4-chlorophenyl)ethyl]-N-(3-fluorocyclobutyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-amine;-   (2R,3R)-1-{2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}-3-ethylazetidine-2-carboxylic    acid;-   2-[1-(4-chlorophenyl)ethyl]-N-[(3,3-difluorocyclobutyl)methyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-amine;-   N-[(3S)-1-{2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}pyrrolidin-3-yl]acetamide;-   cis-3-({2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}amino)cyclobutanol;-   trans-3-({2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}amino)cyclobutanol;-   6-{2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}-6-azaspiro[3.4]octan-1-ol;-   2-[1-(4-chlorophenyl)ethyl]-N-(3,3-difluorocyclobutyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-amine;-   2-[1-(4-chlorophenyl)ethyl]-7-[(2R)-2-ethylpiperidin-1-yl]-5-methylpyrazolo[1,5-a]pyrimidine;-   N-[(3R)-1-{2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}pyrrolidin-3-yl]acetamide;-   2-(1-{2-[1-(4-chlorophenyl)propyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}piperidin-2-yl)ethanol;-   2-[1-(4-chlorophenyl)propyl]-7-(3,3-difluoropiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine;-   2-(1-{2-[1-(4-chlorophenyl)-2-methylpropyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}piperidin-2-yl)ethanol;-   2-[1-(4-chlorophenyl)-2-methylpropyl]-7-(3,3-difluoropiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine;-   2-(1-{2-[1-(4-chlorophenyl)butyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}piperidin-2-yl)ethanol;-   2-[1-(4-chlorophenyl)butyl]-7-(3,3-difluoropiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine;-   2-(1-{5-methyl-2-[3-(trifluoromethyl)benzyl]pyrazolo[1,5-a]pyrimidin-7-yl}piperidin-2-yl)ethanol;-   2-{1-[5-methyl-2-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)pyrazolo[1,5-a]pyrimidin-7-yl]piperidin-2-yl}ethanol;-   (2S)-1-(5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)azetidine-2-carboxamide;-   2-[1-(5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)piperidin-2-yl]ethanol;-   5-methyl-7-(2-oxa-6-azaspiro[3.4]oct-6-yl)-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine;-   5-methyl-7-(7-oxa-2-azaspiro[3.5]non-2-yl)-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine;-   (3R)-1-(5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)piperidin-3-ol;-   N-(3-fluorocyclobutyl)-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-amine;-   N-[(3S)-1-(5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)pyrrolidin-3-yl]acetamide;-   5-methyl-N-(1-methylcyclopropyl)-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-amine;-   [1-(5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)piperidin-2-yl]methanol;-   (2S)-1-(5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)azetidine-2-carboxylic    acid;-   7-(4-fluoropiperidin-1-yl)-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine;-   7-(3-fluoropiperidin-1-yl)-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine;-   3-(2-hydroxyethyl)-4-(5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)piperazin-2-one;-   N-[(3,3-difluorocyclobutyl)methyl]-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-amine;-   7-(3,3-difluoropyrrolidin-1-yl)-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine;-   N-[(3R)-1-(5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)pyrrolidin-3-yl]acetamide;-   7-(3,3-difluoropiperidin-1-yl)-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine;-   1-(5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)piperidin-2-one;-   N-tert-butyl-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-amine;-   N-(3,3-difluorocyclobutyl)-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-amine;-   5-methyl-7-(2-oxa-7-azaspiro[3.5]non-7-yl)-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine;-   1-(5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)pyrrolidine-3-carboxamide;-   (1-{2-[1-(5-chloropyridin-2-yl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}piperidin-3-yl)methanol;-   2-[1-(5-chloropyridin-2-yl)ethyl]-N-(3,3-difluorocyclobutyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-amine;-   (3S)-1-{2-[1-(5-chloropyridin-2-yl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}piperidin-3-ol;-   2-[1-(5-chloropyridin-2-yl)ethyl]-7-(3,3-difluoropiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine;-   2-[1-(5-chloropyridin-2-yl)ethyl]-7-(3,3-difluoropyrrolidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine;-   N-tert-butyl-2-[1-(5-chloropyridin-2-yl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-amine;-   2-[1-(5-chloropyridin-2-yl)ethyl]-5-methyl-N-(1-methylcyclopropyl)pyrazolo[1,5-a]pyrimidin-7-amine;-   2-[1-(5-chloropyridin-2-yl)ethyl]-N-(3-fluorocyclobutyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-amine;-   2-[1-(5-chloropyridin-2-yl)ethyl]-5-methyl-7-(7-oxa-2-azaspiro[3.5]non-2-yl)pyrazolo[1,5-a]pyrimidine;-   N-[(3R)-1-{2-[1-(5-chloropyridin-2-yl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}pyrrolidin-3-yl]acetamide;-   N-[(3S)-1-{2-[1-(5-chloropyridin-2-yl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}pyrrolidin-3-yl]acetamide;-   N-{(3R)-1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]pyrrolidin-3-yl}methanesulfonamide;-   N-{(3S)-1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidin-3-yl}methanesulfonamide;    and-   2-{1-[2-(3-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidin-2-yl}ethanol.

Compound names are assigned by using Name 2014 naming algorithm byAdvanced Chemical Development or Struct=Name naming algorithm as part ofCHEMDRAW® ULTRA v. 12.0.2.1076.

Compounds of the invention may exist as stereoisomers wherein asymmetricor chiral centers are present. These stereoisomers are “R” or “S”depending on the configuration of substituents around the chiral carbonatom. The terms “R” and “S” used herein are configurations as defined inIUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry,in Pure Appl. Chem., 1976, 45: 13-30. The invention contemplates variousstereoisomers and mixtures thereof and these are specifically includedwithin the scope of this invention. Stereoisomers include enantiomersand diastereomers, and mixtures of enantiomers or diastereomers.Individual stereoisomers of compounds of the invention may be preparedsynthetically from commercially available starting materials whichcontain asymmetric or chiral centers or by preparation of racemicmixtures followed by methods of resolution well-known to those ofordinary skill in the art. These methods of resolution are exemplifiedby (1) attachment of a mixture of enantiomers to a chiral auxiliary,separation of the resulting mixture of diastereomers byrecrystallization or chromatography and optional liberation of theoptically pure product from the auxiliary as described in Fumrniss,Hannaford, Smith, and Tatchell, “Vogel's Textbook of Practical OrganicChemistry”, 5th edition (1989), Longman Scientific & Technical, EssexCM20 2JE, England, or (2) direct separation of the mixture of opticalenantiomers on chiral chromatographic columns or (3) fractionalrecrystallization methods.

Compounds of the invention may exist as cis or trans isomers, whereinsubstituents on a ring may attached in such a manner that they are onthe same side of the ring (cis) relative to each other, or on oppositesides of the ring relative to each other (trans). For example,cyclobutane may be present in the cis or trans configuration, and may bepresent as a single isomer or a mixture of the cis and trans isomers.Individual cis or trans isomers of compounds of the invention may beprepared synthetically from commercially available starting materialsusing selective organic transformations, or prepared in single isomericform by purification of mixtures of the cis and trans isomers. Suchmethods are well-known to those of ordinary skill in the art, and mayinclude separation of isomers by recrystallization or chromatography.

It should be understood that the compounds of the invention may possesstautomeric forms, as well as geometric isomers, and that these alsoconstitute an aspect of the invention.

The present disclosure includes all pharmaceutically acceptableisotopically-labelled compounds of formula (I) wherein one or more atomsare replaced by atoms having the same atomic number, but an atomic massor mass number different from the atomic mass or mass number whichpredominates in nature. Examples of isotopes suitable for inclusion inthe compounds of the disclosure include isotopes of hydrogen, such as ²Hand ³H, carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl,fluorine, such as ¹⁸F, iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as¹³N and ¹⁵N, oxygen, such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P,and sulfur, such as ³⁵S. Certain isotopically-labelled compounds offormula (I), for example, those incorporating a radioactive isotope, areuseful in drug and/or substrate tissue distribution studies. Theradioactive isotopes tritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, areparticularly useful for this purpose in view of their ease ofincorporation and ready means of detection. Substitution with heavierisotopes such as deuterium, i.e. ²H, may afford certain therapeuticadvantages resulting from greater metabolic stability, for example,increased in vivo half-life or reduced dosage requirements, and hencemay be preferred in some circumstances. Substitution with positronemitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N, can be useful inPositron Emission Topography (PET) studies for examining substratereceptor occupancy. Isotopically-labeled compounds of formula (I) cangenerally be prepared by conventional techniques known to those skilledin the art or by processes analogous to those described in theaccompanying Examples using an appropriate isotopically-labeled reagentsin place of the non-labeled reagent previously employed.

Thus, the formula drawings within this specification can represent onlyone of the possible tautomeric, geometric, or stereoisomeric forms. Itis to be understood that the invention encompasses any tautomeric,geometric, or stereoisomeric form, and mixtures thereof, and is not tobe limited merely to any one tautomeric, geometric, or stereoisomericform utilized within the formula drawings.

Present compounds may be used in the form of pharmaceutically acceptablesalts. The phrase “pharmaceutically acceptable salt” means those saltswhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like and arecommensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable salts have been described in S. M. Berge etal. J. Pharmaceutical Sciences, 1977, 66: 1-19.

Compounds of the invention may contain either a basic or an acidicfunctionality, or both, and can be converted to a pharmaceuticallyacceptable salt, when desired, by using a suitable acid or base. Thesalts may be prepared in situ during the final isolation andpurification of the compounds of the invention.

Examples of acid addition salts include, but are not limited to acetate,adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate,bisulfate, butyrate, camphorate, camphorsulfonate, digluconate,glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate,hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate(isothionate), lactate, malate, maleate, methanesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate,3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate,thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as lower alkyl halides such as, but notlimited to, methyl, ethyl, propyl, and butyl chlorides, bromides andiodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamylsulfates; long chain halides such as, but not limited to, decyl, lauryl,myristyl and stearyl chlorides, bromides and iodides; arylalkyl halideslike benzyl and phenethyl bromides and others. Water or oil-soluble ordispersible products are thereby obtained. Examples of acids which maybe employed to form pharmaceutically acceptable acid addition saltsinclude such inorganic acids as hydrochloric acid, hydrobromic acid,sulfuric acid, and phosphoric acid and such organic acids as aceticacid, fumaric acid, maleic acid, 4-methylbenzenesulfonic acid, succinicacid and citric acid.

Basic addition salts may be prepared in situ during the final isolationand purification of compounds of this invention by reacting a carboxylicacid-containing moiety with a suitable base such as, but not limited to,the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptablemetal cation or with ammonia or an organic primary, secondary ortertiary amine. Pharmaceutically acceptable salts include, but are notlimited to, cations based on alkali metals or alkaline earth metals suchas, but not limited to, lithium, sodium, potassium, calcium, magnesiumand aluminum salts and the like and nontoxic quaternary ammonia andamine cations including ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine and the like. Other examples oforganic amines useful for the formation of base addition salts includeethylenediamine, ethanolamine, diethanolamine, piperidine, piperazineand the like.

The term “pharmaceutically acceptable prodrug” or “prodrug” as usedherein, represents those prodrugs of the compounds of the inventionwhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, commensurate witha reasonable benefit/risk ratio, and effective for their intended use.

The invention contemplates compounds formed by synthetic means or formedby in vivo biotransformation of a prodrug.

Compounds described herein can exist in unsolvated as well as solvatedforms, including hydrated forms, such as hemi-hydrates. In general, thesolvated forms, with pharmaceutically acceptable solvents such as waterand ethanol among others are equivalent to the unsolvated forms for thepurposes of the invention.

General Synthesis

The compounds of the invention can be better understood in connectionwith the following synthetic schemes and methods which illustrate ameans by which the compounds can be prepared.

The compounds of this invention can be prepared by a variety ofsynthetic procedures. Representative procedures are shown in, but arenot limited to, Schemes 1-2. In Schemes 1-2, the variables R¹, R², R³,R⁴, G¹, and L¹ are as described in the Summary.

As shown in Scheme 1, compounds of formula (1-7) can be preparedstarting from acetonitrile and compounds of formula (1-1). Accordingly,acetonitrile can be treated with a base, such as but not limited ton-butyllithium, in a solvent such as tetrahydrofuran at −70 to −80° C.over 15 to 120 minutes. The anion of acetonitrile can then be reactedwith compounds of formula (1-1) initially at −70 to −80° C. followed bygradual warming over 4 to 24 hours to give compounds of formula (1-2).Compounds of formula (1-2) can be reacted with hydrazine or hydrazinehydrate in ethanol at or near the refluxing temperature over 2 to 8hours to give compounds of formula (1-3). Compounds of formula (1-3) canthen be reacted with compounds of formula (1-4) in acetic acid heatedbetween 90° C. and the reflux temperature over 2 to 8 hours to providecompounds of formula (1-5). Compounds of formula (1-5) can be reactedwith phosphoryl chloride at reflux temperature over 1 to 12 hoursoptionally with a co-solvent such as acetonitrile and optionally in thepresence of a base such as triethylamine to give compounds of formula(1-6). Compounds of formula (1-6) can be reacted with HNR¹R² in thepresence of a base in a heated solvent to give compounds of formula(1-7). Suitable bases for the conversion of compounds of formula (1-6)to compounds of formula (1-7) are potassium carbonate, sodium carbonate,cesium carbonate in the presence of potassium iodide, triethylamine ordiisopropylethylamine. Suitable solvents for the conversion of compoundsof formula (1-6) to compounds of formula (1-7) include but are notlimited to N,N-dimethylformamide, dioxane, ethanol or acetonitrileheated conventionally from 40-135° C. over 4 to 36 hours dependent onthe particular solvent used. The heating can also be achieved withmicrowave irradiation in a sealed vessel heated between 100-160° C. over30 to 150 minutes. Compounds of formula (1-7) are representative ofcompounds of formula (I).

As shown in Scheme 2, compounds of formula (2-2) can be prepared fromcompounds of formula (1-6). Compounds of formula (1-6) can be reactedunder palladium catalyzed cross-coupling reaction conditions with four-to seven-membered lactams of formula (2-1) which are optionallysubstituted as described for R¹ and R². For example, compounds offormula (1-6) can be coupled with compounds of formula (2-1) in thepresence of a palladium catalyst such astris(dibenzylideneacetone)dipalladium(0) (Pd₂(dba)₃) or palladium(II)acetate, a phosphine ligand such as2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos) or(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (Xantphos),and a base such as cesium carbonate heated either conventionally or withmicrowave irradiation in a solvent such as N,N-dimethylformamide ordioxane to give compounds of formula (2-2). Compounds of formula (2-2)are representative of compounds of formula (I).

The compounds and intermediates of the invention may be isolated andpurified by methods well-known to those skilled in the art of organicsynthesis. Examples of conventional methods for isolating and purifyingcompounds can include, but are not limited to, chromatography on solidsupports such as silica gel, alumina, or silica derivatized withalkylsilane groups, by recrystallization at high or low temperature withan optional pretreatment with activated carbon, thin-layerchromatography, distillation at various pressures, sublimation undervacuum, and trituration, as described for instance in “Vogel's Textbookof Practical Organic Chemistry”, 5th edition (1989), by Fumrniss,Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical,Essex CM20 2JE, England.

Many of the compounds of the invention have at least one basic nitrogenwhereby the compound can be treated with an acid to form a desired salt.For example, a compound may be reacted with an acid at or above roomtemperature to provide the desired salt, which is deposited, andcollected by filtration after cooling. Examples of acids suitable forthe reaction include, but are not limited to tartaric acid, lactic acid,succinic acid, as well as mandelic, atrolactic, methanesulfonic,ethanesulfonic, toluenesulfonic, naphthalenesulfonic, benzenesulfonic,carbonic, fumaric, maleic, gluconic, acetic, propionic, salicylic,hydrochloric, hydrobromic, phosphoric, sulfuric, citric, hydroxybutyric,camphorsulfonic, malic, phenylacetic, aspartic, or glutamic acid, andthe like.

Optimum reaction conditions and reaction times for each individual stepcan vary depending on the particular reactants employed and substituentspresent in the reactants used. Unless otherwise specified, solvents,temperatures and other reaction conditions can be readily selected byone of ordinary skill in the art. Specific procedures are provided inthe Examples section. Reactions can be worked up in the conventionalmanner, e.g. by eliminating the solvent from the residue and furtherpurified according to methodologies generally known in the art such as,but not limited to, crystallization, distillation, extraction,trituration and chromatography. Unless otherwise described, the startingmaterials and reagents are either commercially available or can beprepared by one skilled in the art from commercially available materialsusing methods described in the chemical literature.

Routine experimentations, including appropriate manipulation of thereaction conditions, reagents and sequence of the synthetic route,protection of any chemical functionality that cannot be compatible withthe reaction conditions, and deprotection at a suitable point in thereaction sequence of the method are included in the scope of theinvention. Suitable protecting groups and the methods for protecting anddeprotecting different substituents using such suitable protectinggroups are well known to those skilled in the art; examples of which canbe found in P G M Wuts and T W Greene, in Greene's book titledProtective Groups in Organic Synthesis (4^(th) ed.), John Wiley & Sons,NY (2006), which is incorporated herein by reference in its entirety.Synthesis of the compounds of the invention can be accomplished bymethods analogous to those described in the synthetic schemes describedhereinabove and in specific examples.

Starting materials, if not commercially available, can be prepared byprocedures selected from standard organic chemical techniques,techniques that are analogous to the synthesis of known, structurallysimilar compounds, or techniques that are analogous to the abovedescribed schemes or the procedures described in the synthetic examplessection.

When an optically active form of a compound of the invention isrequired, it can be obtained by carrying out one of the proceduresdescribed herein using an optically active starting material (prepared,for example, by asymmetric induction of a suitable reaction step), or byresolution of a mixture of the stereoisomers of the compound orintermediates using a standard procedure (such as chromatographicseparation, recrystallization or enzymatic resolution).

Similarly, when a pure geometric isomer of a compound of the inventionis required, it can be obtained by carrying out one of the aboveprocedures using a pure geometric isomer as a starting material, or byresolution of a mixture of the geometric isomers of the compound orintermediates using a standard procedure such as chromatographicseparation.

It can be appreciated that the synthetic schemes and specific examplesas illustrated in the Examples section are illustrative and are not tobe read as limiting the scope of the invention as it is defined in theappended claims. All alternatives, modifications, and equivalents of thesynthetic methods and specific examples are included within the scope ofthe claims.

Pharmaceutical Compositions

This invention also provides for pharmaceutical compositions comprisinga therapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable salt thereof together with apharmaceutically acceptable carrier, diluent, or excipient thereof. Thephrase “pharmaceutical composition” refers to a composition suitable foradministration in medical or veterinary use.

The pharmaceutical compositions that comprise a compound of formula (I),alone or in combination with a second therapeutic agent, may beadministered to the subjects orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments or drops), bucally or as an oral or nasal spray. Theterm “parenterally” as used herein, refers to modes of administrationwhich include intravenous, intramuscular, intraperitoneal, intrasternal,subcutaneous and intraarticular injection and infusion.

The term “pharmaceutically acceptable carrier” as used herein, means anon-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which may serve as pharmaceutically acceptablecarriers are sugars such as, but not limited to, lactose, glucose andsucrose; starches such as, but not limited to, corn starch and potatostarch; cellulose and its derivatives such as, but not limited to,sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients such as, but notlimited to, cocoa butter and suppository waxes; oils such as, but notlimited to, peanut oil, cottonseed oil, safflower oil, sesame oil, oliveoil, corn oil and soybean oil; glycols; such a propylene glycol; esterssuch as, but not limited to, ethyl oleate and ethyl laurate; agar;buffering agents such as, but not limited to, magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as, but not limitedto, sodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants may also be present inthe composition, according to the judgment of the formulator.

Pharmaceutical compositions for parenteral injection comprisepharmaceutically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions as well as sterile powders forreconstitution into sterile injectable solutions or dispersions justprior to use. Examples of suitable aqueous and nonaqueous carriers,diluents, solvents or vehicles include water, ethanol, polyols (such asglycerol, propylene glycol, polyethylene glycol and the like), vegetableoils (such as olive oil), injectable organic esters (such as ethyloleate), and suitable mixtures thereof. Proper fluidity may bemaintained, for example, by the use of coating materials such aslecithin, by the maintenance of the required particle size in the caseof dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents such as sugars, sodium chloride,and the like. Prolonged absorption of the injectable pharmaceutical formmay be brought about by the inclusion of agents which delay absorption,such as aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it isdesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This may be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of aparenterally-administered drug form may be accomplished by dissolving orsuspending the drug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release may be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations may be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In certain embodiments, solid dosage formsmay contain from 1% to 95% (w/w) of a compound of formula (I). Incertain embodiments, the compound of formula (I) may be present in thesolid dosage form in a range of from 5% to 70% (w/w). In such soliddosage forms, the active compound may be mixed with at least one inert,pharmaceutically acceptable excipient or carrier, such as sodium citrateor dicalcium phosphate and/or a) fillers or extenders such as starches,lactose, sucrose, glucose, mannitol and silicic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate and mixturesthereof. In the case of capsules, tablets and pills, the dosage form mayalso comprise buffering agents.

The pharmaceutical composition may be a unit dosage form. In such formthe preparation is subdivided into unit doses containing appropriatequantities of the active component. The unit dosage form can be apackaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampules. Also, the unit dosage form may be a capsule, tablet, cachet, orlozenge itself, or it may be the appropriate number of any of these inpackaged form. The quantity of active component in a unit dosepreparation may be varied or adjusted from 0.1 mg to 1000 mg, from 1 mgto 100 mg, or from 1% to 95% (w/w) of a unit dose, according to theparticular application and the potency of the active component. Thecomposition may, if desired, also contain other compatible therapeuticagents.

The dose to be administered to a subject may be determined by theefficacy of the particular compound employed and the condition of thesubject, as well as the body weight or surface area of the subject to betreated. The size of the dose also will be determined by the existence,nature, and extent of any adverse side-effects that accompany theadministration of a particular compound in a particular subject. Indetermining the effective amount of the compound to be administered inthe treatment or prophylaxis of the disorder being treated, thephysician may evaluate factors such as the circulating plasma levels ofthe compound, compound toxicities, and/or the progression of thedisease, etc.

For administration, compounds may be administered at a rate determinedby factors that may include, but are not limited to, the LD₅₀ of thecompound, the pharmacokinetic profile of the compound, contraindicateddrugs, and the side-effects of the compound at various concentrations,as applied to the mass and overall health of the subject. Administrationmay be accomplished via single or divided doses.

The compounds utilized in the pharmaceutical method of the invention maybe administered at the initial dosage of about 0.001 mg/kg to about 100mg/kg daily. In certain embodiments, the daily dose range is from about0.1 mg/kg to about 10 mg/kg. The dosages, however, may be varieddepending upon the requirements of the subject, the severity of thecondition being treated, and the compound being employed. Determinationof the proper dosage for a particular situation is within the skill ofthe practitioner. Treatment may be initiated with smaller dosages, whichare less than the optimum dose of the compound. Thereafter, the dosageis increased by small increments until the optimum effect undercircumstances is reached. For convenience, the total daily dosage may bedivided and administered in portions during the day, if desired.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such carriers as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike.

The solid dosage forms of tablets, dragees, capsules, pills and granulescan be prepared with coatings and shells such as enteric coatings andother coatings well-known in the pharmaceutical formulating art. Theymay optionally contain opacifying agents and may also be of acomposition such that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

The active compounds may also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned carriers.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols, and fatty acid esters of sorbitan andmixtures thereof.

Besides inert diluents, the oral compositions may also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.

Compositions for rectal or vaginal administration are preferablysuppositories which may be prepared by mixing the compounds withsuitable non-irritating carriers or carriers such as cocoa butter,polyethylene glycol, or a suppository wax which are solid at roomtemperature but liquid at body temperature and therefore melt in therectum or vaginal cavity and release the active compound.

Compounds may also be administered in the form of liposomes. Liposomesgenerally may be derived from phospholipids or other lipid substances.Liposomes are formed by mono- or multi-lamellar hydrated liquid crystalswhich are dispersed in an aqueous medium. Any non-toxic, physiologicallyacceptable and metabolizable lipid capable of forming liposomes may beused. The present compositions in liposome form may contain, in additionto a compound of the invention, stabilizers, preservatives, excipients,and the like. Examples of lipids include, but are not limited to,natural and synthetic phospholipids, and phosphatidyl cholines(lecithins), used separately or together.

Methods to form liposomes have been described, see example, Prescott,Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y.(1976), p. 33 et seq.

Dosage forms for topical administration of a compound described hereininclude powders, sprays, ointments, and inhalants. The active compoundmay be mixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers or propellants which maybe required. Ophthalmic formulations, eye ointments, powders andsolutions are also contemplated as being within the scope of thisinvention.

Methods of Use

The compounds and compositions using any amount and any route ofadministration may be administered to a subject for the treatment orprevention of pain, substance abuse (especially in alcohol dependence),or spasticity.

The term “administering” refers to the method of contacting a compoundwith a subject. Thus, the compounds may be administered by injection,that is, intravenously, intramuscularly, intracutaneously,subcutaneously, intraduodenally, parentally, or intraperitoneally. Also,the compounds described herein may be administered by inhalation, forexample, intranasally. Additionally, the compounds may be administeredtransdermally, topically, via implantation, transdermally, topically,and via implantation. In certain embodiments, the compounds andcompositions thereof may be delivered orally. The compounds may also bedelivered rectally, bucally, intravaginally, ocularly, or byinsufflation. GABA-B modulated disorders and conditions may be treatedprophylactically, acutely, and chronically using compounds andcompositions thereof, depending on the nature of the disorder orcondition. Typically, the host or subject in each of these methods ishuman, although other mammals may also benefit from the administrationof compounds and compositions thereof as set forth hereinabove.

Compounds of the invention are useful as positive allosteric modulatorsof GABA-B. Thus, the compounds and compositions are particularly usefulfor treating or lessening the severity, or progression of a disease,disorder, or a condition where the GABA-B receptor is involved.Accordingly, the invention provides a method for treating of pain,substance abuse (especially in alcohol dependence), or spasticity in asubject, wherein the method comprises the step of administering to saidsubject a therapeutically effective amount of a compound of formula (I)or a preferred embodiment thereof as set forth above, with or without apharmaceutically acceptable carrier. Particularly, the method is for thetreatment or prevention of pain.

The invention also relates to a compound according to formula (I) or apharmaceutically acceptable salt thereof for use in medicine.

The invention further relates to a compound according to formula (I) ora pharmaceutically acceptable salt thereof for use in the treatment ofpain, substance abuse (especially in alcohol dependence), spasticity,fragile X syndrome, Down's syndrome, autism, retinal ganglion celldegeneration, gastro-esophageal reflux disease (GERD), smokingcessation, addiction of narcotic agents, emesis, cough, overactivebladder, anxiety, migraine or tinnitus.

The invention further relates to the use of a compound according toformula (I) or a pharmaceutically acceptable salt thereof in thepreparation of a medicament.

The invention further relates to the use of a compound according toformula (I) in the preparation of a medicament for use in the treatmentof pain, substance abuse (especially in alcohol dependence), spasticity,fragile X syndrome, Down's syndrome, autism, retinal ganglion celldegeneration, gastro-esophageal reflux disease (GERD), smokingcessation, addiction of narcotic agents, emesis, cough, overactivebladder, anxiety, migraine or tinnitus.

The present compounds may be co-administered to a subject. The term“co-administered” means the administration of two or more differenttherapeutic agents that are administered to a subject by combination inthe same pharmaceutical composition or separate pharmaceuticalcompositions. Thus co-administration involves administration at the sametime of a single pharmaceutical composition comprising two or moretherapeutic agents or administration of two or more differentcompositions to the same subject at the same or different times.

The compounds of the invention may be co-administered with atherapeutically effective amount of one or more agents to treat pain,where examples of the agents include, nonsteroidal anti-inflammatorydrugs (NSAIDs), opioid analgesics, barbiturates, benzodiazapines,histamine antagonists, sedatives, skeletal muscle relaxants, transientreceptor potential ion channel antagonists, α-adrenergics, tricyclicantidepressants, anticonvulsants, tachykinin antagonists, muscarinicantagonists, cyclooxygenase-2 selective inhibitors, neuroleptics,vanilloid receptor agonists, vanilloid receptor antagonists,β-adrenergics, local anesthetics, corticosteroids, 5-HT receptoragonists, 5-HT receptor antagonists, 5-HT_(2A) receptor antagonists,cholinergic analgesics, α₂δ ligands (such as gabapentin or pregabalin),cannabinoid receptor ligands, metabotropic glutamate subtype 1 receptorantagonists, serotonin reuptake inhibitors, norepinephrine reuptakeinhibitors, dual serotonin-noradrenaline reuptake inhibitors, Rho kinaseinhibitors, inducible nitric oxide synthase inhibitors,acetylcholinesterase inhibitors, prostaglandin E₂ subtype 4 antagonists,leukotriene B4 antagonists, 5-lipoxygenase inhibitors, sodium channelblockers, 5-HT₃ antagonists, N-methyl-D-aspartic acid receptorantagonists, phosphodiesterase V inhibitors, voltage-gated calciumchannel blockers (e.g., N-type and T-type), and KCNQ openers (e.g.,KCNQ2/3 (K_(v)7.2/3)).

This invention also is directed to kits that comprise one or morecompounds and/or salts of the invention, and, optionally, one or moreadditional therapeutic agents.

This invention also is directed to methods of use of the compounds,salts, compositions, and/or kits of the invention to, for example,modulate the γ-aminobutyric acid receptor, and treat a disease treatableby modulating the γ-aminobutyric acid receptor (including pain,substance abuse (especially in alcohol dependence), spasticity, fragileX syndrome, Down's syndrome, autism, retinal ganglion cell degeneration,gastro-esophageal reflux disease (GERD), smoking cessation, addiction ofnarcotic agents, emesis, cough, overactive bladder, anxiety, migraine ortinnitus).

This invention also is directed to a use of one or more compounds and/orsalts of the invention in the preparation of a medicament. Themedicament optionally can comprise one or more additional therapeuticagents. In some embodiments, the medicament is useful for treating pain,substance abuse (especially in alcohol dependence), spasticity, fragileX syndrome, Down's syndrome, autism, retinal ganglion cell degeneration,gastro-esophageal reflux disease (GERD), smoking cessation, addiction ofnarcotic agents, emesis, cough, overactive bladder, anxiety, migraine ortinnitus.

This invention also is directed to a use of one or more compounds and/orsalts of the invention in the manufacture of a medicament for thetreatment of pain, substance abuse (especially in alcohol dependence),spasticity, fragile X syndrome, Down's syndrome, autism, retinalganglion cell degeneration, gastro-esophageal reflux disease (GERD),smoking cessation, addiction of narcotic agents, emesis, cough,overactive bladder, anxiety, migraine or tinnitus. The medicamentoptionally can comprise one or more additional therapeutic agents.

Further benefits of Applicants' invention will be apparent to oneskilled in the art from reading this patent application.

The following Examples may be used for illustrative purposes and shouldnot be deemed to narrow the scope of the invention.

EXAMPLES

Abbreviations: d for day; h for hour; DMSO for dimethyl sulfoxide; ESIfor electrospray ionization; Et for ethyl; LC-MS for liquidchromatography/mass spectrometry; room temperature (20-25° C.);

I. Preparation of Intermediates

The starting materials used in the examples are either commerciallyavailable or can be synthesized by the average skilled person trained inorganic chemistry following routine laboratory practice as outlined, forexample in the examples below.

Intermediate a1:7-chloro-2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidine a1.1)3-(4-chlorobenzyl)-1H-pyrazol-5-amine

A mixture of 4-(4-chlorophenyl)-3-oxobutanenitrile (1955 mg, 10.10 mmol)and hydrazine monohydrate (1011 mg, 20.19 mmol) in ethanol (30 mL) wasrefluxed for 3 h. For work-up, the reaction mixture was partitionedbetween water and ethyl acetate. The combined organic layers were washedwith 50% aqueous NaHCO₃ solution and brine, dried over MgSO₄, andconcentrated in vacuo to give the titled compound (1.6 g, 76%). LC-MS(ESI+) m/z 208.1 [M+H]⁺.

a1.2) 2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-ol

A mixture of compound a1.1 (1.6 g, 7.70 mmol) and ethyl 3-oxobutanoate(1.504 g, 11.56 mmol) in acetic acid (30 mL) was refluxed for 3 h. Then,the reaction mixture was concentrated, and the residue was dissolved indichloromethane. The resultant solid was collected by filtration anddried in vacuo overnight to give the titled compound (2.10 g, 100%).LC-MS (ESI+) m/z 274.1 [M+H]⁺.

a1.3) 7-chloro-2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidine

A mixture of compound a1.2 (2.1 g, 7.67 mmol) in phosphoryl trichloride(24.68 g, 15 mL, 161 mmol) was refluxed for 2 h. The reaction mixturewas then slowly poured into water (exothermic reaction) with atemperature increase from room temperature to 35° C. observed. Thesolution was extracted with dichloromethane, and the organic layers weredried over MgSO₄ and concentrated. The residue was dissolved in ethylacetate, and the insoluble residues (R1) were filtered off. The filtrate(F1) was concentrated, and the residue was triturated with ethylacetate:diisopropyl ether (1:1) to separate the remaining solids (R2)from the triturate (F2). R1 and F2 were combined and purifiedchromatographically using a Teledyne Isco RediSep® silica gel cartridge(12 g) on a Teledyne Isco CombiFlash® system eluted with 20% ethylacetate/cyclohexane (27 mL/minute) to obtain the titled compound (1.6 g,71.4%). LC-MS (ESI+) m/z 292.0 [M+H]⁺.

Intermediate a2)7-chloro-2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidinea2.1) 4-(4-chlorophenyl)-3-oxopentanenitrile

A solution of butyllithium (1.6 M in hexane, 8.65 mL, 0.887 g, 13.84mmol) in tetrahydrofuran (30 mL) was cooled to −75° C., and a solutionof acetonitrile (0.568 g, 13.84 mmol) in tetrahydrofuran (3 mL) wasadded dropwise. After addition, the solution was stirred for another 90minutes at −75° C. To the obtained white suspension, a solution ofmethyl 2-(4-chlorophenyl)propanoate (2.50 g, 12.59 mmol) intetrahydrofuran (10 mL) was added at −75° C., and the reaction mixturewas stirred overnight and allowed to warm to room temperature. Themixture was then partitioned between 80% aqueous NH₄Cl solution andethyl acetate. The organic phases were washed with water and brine,dried over MgSO₄, filtered, and concentrated in vacuo to give the titledcompound (2.45 g, 94%). LC-MS (ESI+) m/z 208.1 [M+H]⁺.

a2.2) 3-[1-(4-chlorophenyl)ethyl]-1H-pyrazol-5-amine

The synthesis was done analogously to the synthesis of intermediate a1.1to give the titled compound (100%). LC-MS (ESI+) m/z 222.1 [M+H]⁺.

a2.3) 2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-ol

The reaction was done analogously to the synthesis of intermediate a1.2.For workup, the reaction mixture was stirred with water (60 mL) anddiisopropyl ether (20 mL). The resultant solids were collected byfiltration, washed with additional diisopropyl ether, and dried in avacuum oven overnight to give the titled compound (63.3%). LC-MS (ESI+)m/z 288.0 [M+H]⁺.

a2.4)7-chloro-2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidine

A mixture of compound a2.3 (2.4 g, 8.34 mmol) and phosphoryl trichloride(3.84 g, 2.33 mL, 25.02 mmol) in acetonitrile (15 mL) was refluxed for 8h. The reaction mixture was quenched with water. The mixture was thenpartitioned between ethyl acetate and 50% aqueous sodium bicarbonate.The organic fraction was washed with 50% aqueous sodium bicarbonate,dried over MgSO₄, and concentrated. The residue was purifiedchromatographically using a Teledyne Isco RediSep® silica gel cartridge(40 g) on a Teledyne Isco CombiFlash® system eluted with a gradient of2-3.5% methanol/dichloromethane (35 mL/minute) to obtain the titledcompound (2.4 g, 94%). LC-MS (ESI+) m/z 306.0 [M+H]⁺.

Intermediate a3)7-chloro-2-[1-(4-chlorophenyl)propyl]-5-methylpyrazolo[1,5-a]pyrimidinea3.1) 4-(4-chlorophenyl)-3-oxohexanenitrile

A solution of butyllithium (6.57 mL, 10.34 mmol, 1.6 M in hexane) intetrahydrofuran (30 mL) was cooled to −75° C., and at this temperature,a solution of acetonitrile (0.540 mL, 10.34 mmol) in tetrahydrofuran (3mL) was added dropwise. The resultant mixture was stirred for 90 minutesat −75° C. producing a white suspension. Then a solution of methyl2-(4-chlorophenyl)butanoate (2.00 g, 9.40 mmol) in tetrahydrofuran (10mL) was slowly added at −75° C., and the reaction mixture was allowed togradually warm to ambient temperature with continued stirring overnight.The reaction mixture was then partitioned between ethyl acetate and 80%aqueous ammonium chloride. The ethyl acetate fraction was subsequentlywashed with water and brine, dried over magnesium sulfate, and filtered.The filtrate was concentrated under reduced pressure to provide thetitled compound (2.1 g, 100%). MS (ESI+) m/z 222.1 [M+H]⁺.

a3.2) 3-[1-(4-chlorophenyl)propyl]-1H-pyrazol-5-amine

A mixture of 4-(4-chlorophenyl)-3-oxohexanenitrile (2.1 g, 9.47 mmol,a3.1), hydrazine hydrate (0.929 mL, 18.95 mmol), and ethanol (30 mL) wasstirred at the reflux temperature for 3 hours. The reaction mixture wasthen partitioned between ethyl acetate and water. The organic phase wassubsequently washed with saturated aqueous sodium bicarbonate solutionand brine, dried over magnesium sulfate, and filtered. The filtrate wasconcentrated under reduced pressure to provide the titled compound (2.6g, 100%). LC-MS (ESI+) m/z 236.1 [M+H]⁺.

a3.3) 2-[1-(4-chlorophenyl)propyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-ol

A mixture of 3-[1-(4-chlorophenyl)propyl]-1H-pyrazol-5-amine (2.23 g,9.46 mmol, a3.2), ethyl acetoacetate (1.795 mL, 14.19 mmol), and aceticacid (30 mL) was stirred for 3 hours at the reflux temperature. Thereaction mixture was partitioned between water (60 mL) and ethyl acetate(20 mL). The organic fraction was subsequently washed with water and 50%aqueous sodium bicarbonate. A precipitate was noted in the organicfraction. The organic fraction was concentrated under reduced pressure,and the residue was stirred with diisopropyl ether. The resultant solidwas collected by filtration, washed with diisopropyl ether, and driedovernight in a vacuum oven at 40° C. to give the titled compound (1.785g, 62.5%). LC-MS (ESI+) m/z 302.2 [M+H]⁺.

a3.4)7-chloro-2-[1-(4-chlorophenyl)propyl]-5-methylpyrazolo[1,5-a]pyrimidine

A mixture of2-[1-(4-chlorophenyl)propyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-ol(1.785 g, 5.92 mmol, a3.3), phosphoryl trichloride (1.654 mL, 17.75mmol) and acetonitrile (30 mL) was stirred at the reflux temperature for8 hours. The reaction was quenched with water. The mixture waspartitioned between a 50% aqueous sodium bicarbonate solution and ethylacetate. The organic phase was then washed with 50% aqueous sodiumbicarbonate solution, dried over MgSO₄, and concentrated under reducedpressure. The residue was chromatographically purified (Teledyne IscoCombiFlash® Rf, 40 g RediSep® silica gel cartridge eluted with a lineargradient of 2-3.5% methanol/dichloromethane over 7 minutes, flow rate 35mL/minute) to provide the titled compound (1.8 g, 95%). LC-MS (ESI⁺) m/z320.2 [M+H]⁺.

Intermediate a4)7-chloro-2-[1-(4-chlorophenyl)-2-methylpropyl]-5-methylpyrazolo[1,5-a]pyrimidinea4.1) 4-(4-chlorophenyl)-5-methyl-3-oxohexanenitrile

The synthesis was done analogously to the synthesis of intermediate a2.1to give the titled compound (100%).

a4.2) 3-[1-(4-chlorophenyl)-2-methylpropyl]-1H-pyrazol-5-amine

The synthesis was done analogously to the synthesis of intermediate a1.1to give the titled compound (100%). LC-MS (ESI+) m/z 250.2 [M+H]⁺.

a4.3)2-[1-(4-chlorophenyl)-2-methylpropyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-ol

The synthesis was done analogously to the synthesis of intermediatea3.3. For workup, the reaction mixture was partitioned between water andethyl acetate. The organic fraction was washed with brine, dried overMgSO₄, filtered, and concentrated. The residue was chromatographicallypurified (Teledyne Isco CombiFlash® Rf, 40 g RediSep® silica gelcartridge eluted with a linear gradient of 2-3.5%methanol/dichloromethane, flow rate 35 mL/minute) to provide the titledcompound (55.2%). MS (ESI+) m/z 316.2 [M+H]⁺.

a4.4)7-chloro-2-[1-(4-chlorophenyl)-2-methylpropyl]-5-methylpyrazolo[1,5-a]pyrimidine

The synthesis and extractive workup were done analogously to thesynthesis of intermediate a3.4. The resultant residue waschromatographically purified (Teledyne Isco CombiFlash® Rf, 24 gRediSep® silica gel cartridge eluted with a linear gradient of 2-3.5%methanol/dichloromethane, flow rate 28 mL/minute) to provide the titledcompound (63.0%) which was stored in a refrigerator. LC-MS (ESI+) m/z334.2 [M+H]⁺.

Intermediate a5)7-chloro-2-[1-(4-chlorophenyl)butyl]-5-methylpyrazolo[1,5-a]pyrimidine

The synthesis was done analogously to the synthesis of INTERMEDIATE a2.The titled compound was obtained as yellow oil that was stored in therefrigerator. LC-MS (ESI+) m/z 334.2 [M+H]⁺.

Intermediate a6:7-chloro-5-methyl-2-[3-(trifluoromethyl)benzyl]pyrazolo[1,5-a]pyrimidinea6.1) 3-oxo-4-[3-(trifluoromethyl)phenyl]butanenitrile

A solution of butyllithium (1.6 M in hexane, 8.02 mL, 12.83 mmol) intetrahydrofuran (30 mL) was cooled to −75° C., and a solution ofacetonitrile (0.737 mL, 13.84 mmol) in tetrahydrofuran (3 mL) was addeddropwise. After addition, the solution was stirred for another 90minutes at −75° C. To the obtained white suspension, a solution ofmethyl 2-(3-(trifluoromethyl)phenyl)acetate (2.80 g, 12.83 mmol) intetrahydrofuran (10 mL) was added at −75° C., and the reaction mixturewas stirred overnight and allowed to warm to room temperature. Themixture was then partitioned between 80% aqueous NH₄Cl solution andethyl acetate. The combined organic phases were washed with water andbrine, dried over MgSO₄, filtered, and concentrated in vacuo. Theresidue was purified chromatographically using a Teledyne Isco RediSep®silica gel cartridge (24 g) on a Teledyne Isco CombiFlash® system elutedwith 25% ethyl acetate/cyclohexane (28 mL/minute) to obtain the titledcompound (1.0 g, 34.3%). LC-MS (ESI+) m/z 250.0 [M+Na]⁺.

a6.2) 3-[3-(trifluoromethyl)benzyl]-1H-pyrazol-5-amine

The synthesis was done analogously to the synthesis of intermediatea1.1. The titled compound was obtained as brown solid (100%). LC-MS(ESI+) m/z 242.0 [M+H]⁺.

a6.3)5-methyl-2-[3-(trifluoromethyl)benzyl]pyrazolo[1,5-a]pyrimidin-7-ol

A mixture of compound a6.2 (1060 mg, 4.39 mmol) and ethyl 3-oxobutanoate(858 mg, 6.59 mmol) in acetic acid (10 mL) was refluxed for 3 h. Forwork-up, the reaction mixture was poured in water (40 mL), and theprecipitate was collected by filtration and washed with diisopropylether. The titled compound was obtained after drying in vacuo as a solid(1030 mg, 76%). LC-MS (ESI+) m/z 308.1 [M+H]⁺.

a6.4)7-chloro-5-methyl-2-[3-(trifluoromethyl)benzyl]pyrazolo[1,5-a]pyrimidine

A mixture of compound a6.3 (1020 mg, 3.32 mmol) and phosphoryltrichloride (1018 mg, 0.619 mL, 6.64 mmol) in acetonitrile (15 mL) wasrefluxed for 8 h. For work-up, water was added to the reaction mixture,and the mixture was partitioned between 50% aqueous NaHCO₃ solution andethyl acetate. The organic layers were washed with 50% aqueous NaHCO₃,dried over MgSO₄, and concentrated in vacuo. The residue was purifiedchromatographically using a Teledyne Isco RediSep® silica gel cartridge(12 g) on a Teledyne Isco CombiFlash® system eluted with a gradient of2-5% methanol/dichloromethane (30 mL/minute) to obtain the titledcompound (880 mg, 81%). LC-MS (ESI+) m/z 326.0 [M+H]⁺.

Intermediate a7:7-chloro-5-methyl-2-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)pyrazolo[1,5-a]pyrimidinea7.1) 3-oxo-4-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)butanenitrile

A solution of butyllithium (1.6 M in hexane, 6.00 mL, 9.60 mmol) intetrahydrofuran (30 mL) was cooled to −75° C., and a solution ofacetonitrile (0.552 mL, 10.56 mmol) in tetrahydrofuran (3 mL) was addeddropwise. After addition, the solution was stirred for another 90minutes at −75° C. To the obtained white suspension, a solution ofmethyl 2-(adamantan-1-yl)acetate (2.00 g, 9.60 mmol) in tetrahydrofuran(10 mL) was added at −75° C., and the reaction mixture was stirredovernight and allowed to warm to room temperature. The mixture was thenpartitioned between 80% aqueous NH₄Cl solution and ethyl acetate. Theorganic phases were washed with water and brine, dried over MgSO₄,filtered, and concentrated in vacuo. The residue was purifiedchromatographically using a Teledyne Isco RediSep® silica gel cartridge(40 g) on a Teledyne Isco CombiFlash® system eluted with 25% ethylacetate/cyclohexane (28 mL/minute) to obtain the titled compound (780mg, 37.4%). LC-MS (ESI+) m/z 218.2 [M+H]⁺.

a7.2) 3-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-5-amine

The synthesis was done analogously to the synthesis of intermediatea1.1. The titled compound was obtained as an off-white solid (100%).LC-MS (ESI+) m/z 232.2 [M+H]⁺.

a7.3)5-methyl-2-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)pyrazolo[1,5-a]pyrimidin-7-ol

A mixture of compound a7.2 (830 mg, 3.59 mmol) and ethyl 3-oxobutanoate(700 mg, 5.38 mmol) in acetic acid (10 mL) was refluxed for 3 h. Forworkup, the reaction mixture was stirred with water (40 mL). Theresultant solids were collected by filtration, washed with diisopropylether, and dried in a vacuum oven overnight to give the titled compound(900 mg, 84%). LC-MS (ESI+) m/z 298.2 [M+H]⁺.

a7.4)7-chloro-5-methyl-2-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)pyrazolo[1,5-a]pyrimidine

A mixture of compound a7.3 (900 mg, 3.03 mmol) and phosphoryltrichloride (928 mg, 0.564 mL, 6.05 mmol) in acetonitrile (15 mL) wasrefluxed for 8 h. Water was then added to the reaction mixture. Themixture was then partitioned between ethyl acetate and 50% aqueoussodium bicarbonate. The organic fraction was washed with 50% aqueoussodium bicarbonate, dried over MgSO₄, and concentrated. The residue waspurified chromatographically using a Teledyne Isco RediSep® silica gelcartridge (12 g) on a Teledyne Isco CombiFlash® system eluted with agradient of 2-5% methanol/dichloromethane (30 mL/minute) to obtain thetitled compound (650 mg, 71.1%). LC-MS (ESI+) m/z 316.2 [M+H]⁺.

Intermediate a8):7-chloro-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidinea8.1) ethyl 2-[4-(trifluoromethyl)phenyl]propanoate

Sodium bis(trimethylsilyl)amide (1.895 g, 10.34 mmol) was added dropwiseinto a solution of ethyl [4-(trifluoromethyl)phenyl]acetate (2.0 g, 8.61mmol) in tetrahydrofuran (40 mL) at −78° C. under an atmosphere ofnitrogen. After stirring for 10 minutes, a solution of iodomethane(1.345 g, 9.47 mmol) in tetrahydrofuran (3 mL) was added. The reactionmixture was stirred at −50° C. for 2 hours. Water and ethyl acetate wereadded, the organic layer was separated, and the aqueous layer wasextracted with ethyl acetate. The combined organic layers were washedwith water and dried over sodium sulfate. After filtration andconcentration under reduced pressure, the crude product was distilledunder vacuum to give the titled compound (1.6 g, 75%). ¹H NMR (400 MHz,CDCl₃) δ ppm 1.21 (t, 3H), 1.51 (d, 3H), 3.77 (q, 1H), 4.15 (m, 2H),7.42 (d, 2H), 7.57 (d, 2H).

a8.2) 3-oxo-4-[4-(trifluoromethyl)phenyl]pentanenitrile

Acetonitrile (0.367 g, 8.93 mmol) was added dropwise into the solutionof butyllithium (0.572 g, 8.93 mmol) in tetrahydrofuran (5 mL) at −78°C. under an atmosphere of nitrogen. After stirring for 2 hours at −78°C., ethyl 2-[4-(trifluoromethyl)phenyl]propanoate (2.0 g, 8.12 mmol,a8.1) was added dropwise. The temperature was allowed to gradually ariseto room temperature. Water and ethyl acetate were added, the organiclayer was separated, and the aqueous layer was extracted with ethylacetate. The combined organic layers were washed with water, dried oversodium sulfate, and concentrated under vacuum. The residue was distilledunder reduced pressure to give the titled compound (1.8 g, 92%), whichwas used to the next step without further purification. MS (ESI+) m/z242.1 [M+H]⁺.

a8.3) 5-{1-[4-(trifluoromethyl)phenyl]ethyl}-1H-pyrazol-3-amine

Hydrazine hydrate (0.374 g, 7.46 mmol) was added to a solution of3-oxo-4-[4-(trifluoromethyl)phenyl]pentanenitrile (1.8 g, 7.46 mmol,a8.2) in ethanol (20 mL). The resulting mixture was stirred at 80° C.for 4 hours. Concentration under vacuum gave the titled compound (1.7 g,89%), which was used directly to the next step without furtherpurification. MS (ESI+) m/z 256.0 [M+H]⁺.

a8.4)5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-ol

Into a solution of5-{1-[4-(trifluoromethyl)phenyl]ethyl}-1H-pyrazol-3-amine (1.7 g, 6.66mmol, a8.3) in acetic acid (20 mL) was added ethyl 3-oxobutanoate (0.953g, 7.33 mmol). The resulting mixture was stirred at 100° C. for 4 hours.After concentration under vacuum, the residue was washed with water anddried in vacuo to afford the titled compound (1.7 g, 79%). MS (ESI+) m/z322.1 [M+H]⁺.

a8.5)7-chloro-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine

5-Methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-ol(1.7 g, 5.29 mmol, a8.4) in phosphoryl trichloride (1.623 g, 10.58 mmol)and triethylamine (0.811 mL, 5.82 mmol) was heated to reflux for 2hours. The reaction mixture was concentrated under vacuum, and theresidue was poured into water/ice (50 mL). The resultant solid wascollected by filtration and washed with hexane to give the titledcompound (1.7 g, 95%). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.76 (d, 3H), 2.57(s, 3H), 4.49 (q, 1H), 6.43 (s, 1H), 6.79 (s, 1H), 7.45 (d, 2H), 7.55(d, 2H).

Intermediate a9):7-chloro-2-[1-(5-chloropyridin-2-yl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidinea9.1) methyl 2-(5-chloropyridin-2-yl)propanoate

2-Bromo-5-chloropyridine (1 g, 5.20 mmol) was added to a suspension ofmethyl 2-bromopropanoate (0.955 g, 5.72 mmol) and copper (0.759 g, 11.95mmol) in dimethyl sulfoxide (5 mL). The mixture was stirred at 50° C.for 2 hours. After cooling to room temperature, the reaction mixture wasdiluted with ethyl acetate (30 mL). An aqueous solution of potassiumdihydrogenphosphate (0.707 g, 5.20 mmol, 15 mL) was added, and themixture stirred for 30 minutes before filtering. The copper salts werewashed with ethyl acetate. The organic layer was washed with water,dried over sodium sulfate, filtered, and concentrated in vacuum.Purification by flash chromatography (petroleum ether/ethyl acetate)provided the titled compound (500 mg, 48.2%). MS (ESI+) m/z 200.0[M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.55 (d, 3H), 3.69 (s, 3H), 3.95(q, 1H), 7.25 (d, 1H), 7.65 (d, 1H), 8.51 (s, 1H).

a9.2) 4-(5-chloropyridin-2-yl)-3-oxopentanenitrile

Acetonitrile (103 mg, 2.505 mmol) was added dropwise into the solutionof butyllithium (2 mL, 0.90 equivalents) in tetrahydrofuran (10 mL) at−78° C. under an atmosphere of nitrogen. After stirring for 0.5 hours at−78° C., methyl 2-(5-chloropyridin-2-yl)propanoate (500 mg, 2.505 mmol,a9.1) in tetrahydrofuran (5 mL) was added dropwise. The temperature wasallowed to gradually rise to room temperature. The resulting solutionwas stirred overnight at room temperature and then quenched by theaddition of water. The pH value of the solution was adjusted to 5 with 1N hydrochloric acid. The resulting solution was extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate and concentrated under vacuum. Purification byflash chromatography (petroleum ether/ethyl acetate) provided the titledcompound (400 mg, 77%). MS (ESI+) m/z 209.0 [M+H]⁺.

a9.3) 5-[1-(5-chloropyridin-2-yl)ethyl]-1H-pyrazol-3-amine

Hydrazine hydrate (3.60 g, 71.9 mmol) was added to a solution of4-(5-chloropyridin-2-yl)-3-oxopentanenitrile (5 g, 23.96 mmol, a9.2) inethanol (20 mL). The resulting solution was stirred at 80° C. for 4hours. After cooled to room temperature, the resulting mixture wasconcentrated under vacuum. This provided the titled compound (3 g,56.2%). MS (ESI+) m/z 223.0 [M+H]⁺.

a9.4)2-[1-(5-chloropyridin-2-yl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-ol

5-[1-(5-Chloropyridin-2-yl)ethyl]-1H-pyrazol-3-amine (4 g, 17.96 mmol,a9.3) in acetic acid (20 mL) was treated with ethyl 3-oxobutanoate (7.01g, 53.9 mmol). The resulting solution was stirred at 100° C. for 4hours. The resulting mixture was concentrated under vacuum, and theresidue was washed with ethyl acetate to provide the titled compound (4g, 77%). MS (ESI+) m/z 289.0 [M+H]⁺.

a9.5)7-chloro-2-[1-(5-chloropyridin-2-yl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidine

Into a solution of2-[1-(5-chloropyridin-2-yl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-ol(2 g, 6.93 mmol, a9.4) in phosphoryl trichloride (3.19 g, 20.78 mmol),triethylamine (2.103 g, 20.78 mmol) was added. The resulting solutionwas stirred at 100° C. for 2 hours. The reaction mixture wasconcentrated under vacuum. The crude product was washed with ethylacetate. The solid was collected and dried in vacuo to provide thetitled compound (200 mg, 9.4%). MS (ESI+) m/z 309.0 [M+H]⁺.

Intermediate a10):(3R)-1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]pyrrolidin-3-aminea10.1) tert-butyl{(3R)-1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]pyrrolidin-3-yl}carbamate

7-Chloro-2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidine (500 mg,1.711 mmol. INTERMEDIATE a1) was added to a suspension of tert-butyl(3R)-pyrrolidin-3-ylcarbamate (319 mg, 1.711 mmol) and potassiumcarbonate (237 mg, 1.711 mmol) in N,N-dimethylformamide (10 mL). Themixture was stirred at 65° C. for 3 hours. Water and ethyl acetate wereadded, the organic layer was separated, and the aqueous layer wasextracted with ethyl acetate. The combined organic layers were washedwith water and dried over sodium sulfate. Purification by flashchromatography (petroleum ether/ethyl acetate) provided the titledcompound (450 mg, 59.4%). MS (ESI+) m/z 442.1 [M+H]⁺; ¹H NMR (400 MHz,CD₃OD) δ ppm 1.44 (s, 9H), 1.99 (m, 1H), 2.21 (m, 1H), 2.34 (s, 3H),3.94 (m, 3H), 4.02 (s, 2H), 4.22 (m, 2H), 5.74 (s, 1H), 5.94 (s, 1H),7.26 (m, 4H).

a10.2)(3R)-1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]pyrrolidin-3-amine

tert-Butyl{(3R)-1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]pyrrolidin-3-yl}carbamate(80 mg, 0.181 mmol, a10.1) in dichloromethane (5 mL) was treated with2,2,2-trifluoroacetic acid (2 mL). The reaction mixture was stirred atroom temperature for 3 hours and then concentrated under vacuum. Thecrude product was purified by flash chromatography, C18 column(acetonitrile/water, 3:1 v/v) to provide the titled compound (20.8 mg,33.6%). MS (ESI+) m/z 342.0 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 1.91(m, 1H), 2.23 (m, 1H), 2.38 (s, 3H), 3.68 (m, 1H), 3.91 (m, 2H), 4.08(m, 3H), 4.21 (m, 1H), 5.76 (s, 1H), 5.98 (s, 1H), 7.29 (m, 4H).

Intermediate a11):(3S)-1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidin-3-aminea11.1) tert-butyl{(3S)-1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidin-3-yl}carbamate

7-Chloro-2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidine (500 mg,1.711 mmol, INTERMEDIATE a1) was added to a suspension of tert-butyl(3S)-piperidin-3-ylcarbamate (377 mg, 1.883 mmol) and potassiumcarbonate (237 mg, 1.711 mmol) in N,N-dimethylformamide (6 mL). Themixture was stirred at 50° C. overnight. Water and ethyl acetate wereadded, the organic layer was separated, and the aqueous layer wasextracted with ethyl acetate. The combined organic layers were washedwith water and dried over sodium sulfate. Purification by flashchromatography (petroleum ether/ethyl acetate) provided the titledcompound (430 mg, 55.1%). A 30 mg aliquot of the titled compound wasfurther purified by preparative-HPLC, Column: Waters XBridge® C18,19×150 mm, 5 μm; Mobile Phase A: water/10 mM NH₄HCO₃, Mobile Phase B:acetonitrile; Flow rate: 20 mL/minute; Gradient: 30% B to 70% B in 10minutes; 254 nm. MS (ESI+) m/z 456.1 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δppm 1.38 (s, 9H), 1.61 (m, 2H), 1.84 (m, 2H), 2.38 (s, 3H), 3.03 (t,2H), 3.55 (m, 1H), 4.05 (s, 2H), 4.18 (m, 2H), 6.13 (s, 1H), 6.24 (s,1H), 7.01 (brs, 1H), 7.33 (m, 4H).

a11.2)(3S)-1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidin-3-amine

tert-Butyl{(3S)-1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidin-3-yl}carbamate(400 mg, 0.877 mmol, a11.1) in N,N-dimethylformamide (5 mL) was treatedwith 2,2,2-trifluoroacetic acid (100 mg, 0.877 mmol). The mixture wasstirred at room temperature overnight and then concentrated undervacuum. The crude material (280 mg, 90%) was used for next step directlywithout further purification. A 30 mg aliquot of the crude material waspurified by preparative-HPLC, Column: Waters XBridge® C18, 19×150 mm, 5m; Mobile Phase A: water/10 mM NH₄HCO₃, Mobile Phase B: acetonitrile;Flow rate: 20 mL/minute; Gradient: 30% B to 70% B in 10 minutes; 254 nm,afforded the titled compound (13.6 mg). MS (ESI+) m/z 356.1 [M+H]⁺; ¹HNMR (400 MHz, CD₃OD) δ ppm 1.50 (m, 1H), 1.75 (m, 1H), 1.90 (m, 1H),2.02 (m, 1H), 2.44 (s, 3H), 3.19 (m, 3H), 4.07 (m, 4H), 6.11 (s, 1H),6.20 (s, 1H), 7.28 (m, 4H).

Intermediate a12):7-chloro-2-(3-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidine a12.1)4-(3-chlorophenyl)-3-oxobutanenitrile

A solution of butyllithium (1.6 M in hexane, 8.12 mL, 0.833 g, 13.0mmol) in tetrahydrofuran (30 mL) was cooled to −75° C., and a solutionof acetonitrile (0.747 mL, 0.587 g, 14.3 mmol) in tetrahydrofuran (3 mL)was added dropwise. After addition, the solution was stirred for another90 minutes at −75° C. To the obtained white suspension, a solution ofmethyl 2-(3-chlorophenyl)acetate (2.40 g, 13.0 mmol) in tetrahydrofuran(10 mL) was added at −75° C., and the reaction mixture was stirredovernight and allowed to warm to room temperature. The mixture was thenpartitioned between 80% aqueous NH₄Cl solution and ethyl acetate. Theorganic phases were washed with water and brine, dried over MgSO₄,filtered, and concentrated. The residue was chromatographically purifiedusing a Teledyne Isco CombiFlash® system (normal phase: 24 g column,eluent: 25% ethyl acetate/cyclohexane) to give the titled compound (1.47g, 58%). LC-MS (ESI+) m/z 194.0 [M+H]⁺.

a12.2) 3-(3-chlorobenzyl)-1H-pyrazol-5-amine

A mixture of 4-(3-chlorophenyl)-3-oxobutanenitrile (1.47 g, 7.59 mmol)and hydrazine monohydrate (0.745 mL, 0.760 g, 15.18 mmol) in ethanol (20mL) was refluxed for 3 h. For work-up, the reaction mixture waspartitioned between water and ethyl acetate. The combined organic layerswere washed with 50% aqueous NaHCO₃ solution and brine, dried overMgSO₄, and concentrated in vacuo. The residue was stirred in a mixtureof ethyl acetate/diisopropyl ether (1:1), and the solid was collected byvacuum filtration and dried in a vacuum oven overnight to give thetitled compound (772 mg, 49.0%). LC-MS (ESI+) m/z 208.1 [M+H]⁺.

a12.3) 2-(3-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-ol

A mixture of compound a12.2 (772 mg, 3.72 mmol) and ethyl 3-oxobutanoate(0.705 mL, 726 mg, 5.58 mmol) in acetic acid (10 mL) was refluxed for 3h. Then, the reaction mixture was diluted with water (40 mL), and theresultant precipitate was collected by vacuum filtration. The collectedsolid was washed with diisopropyl ether and dried overnight in a vacuumoven to give the titled compound (1.00 g, 98%). LC-MS (ESI+) m/z 274.0[M+H]⁺.

a12.4) 7-chloro-2-(3-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidine

A mixture of compound a12.3 (1.00 g, 3.65 mmol) and phosphoryltrichloride (1.12 g, 0.681 mL, 7.31 mmol) in acetonitrile (15 mL) wasrefluxed for 8 h. The reaction mixture was quenched with water. Themixture was then partitioned between ethyl acetate and 50% aqueoussodium bicarbonate. The organic fraction was washed with 50% aqueoussodium bicarbonate, dried over MgSO₄, and concentrated. The residue waspurified chromatographically using a Teledyne Isco RediSep® silica gelcartridge (12 g) on a Teledyne Isco CombiFlash® system eluted with agradient of 2-5% methanol/dichloromethane (30 mL/minute) to obtain thetitled compound (750 mg, 70.3%). LC-MS (ESI+) m/z 292.0 [M+H]⁺.

II. EXAMPLE COMPOUNDS Preparation of Compounds Derived from Intermediatea1 Example 1-12-{1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidin-2-yl}ethanol

A mixture of INTERMEDIATE a1 (50 mg, 0.171 mmol),2-(piperidin-2-yl)ethanol (33.25 mg, 0.25675 mmol), andN-ethyl-N-isopropylpropan-2-amine (33.2 mg, 0.257 mmol) in ethanol (3mL) was stirred at room temperature. After 12 h, additional2-(piperidin-2-yl)ethanol (99.75 mg, 0.77025 mmol) was added andstirring was continued for another 3 d.

For work-up, the reaction mixture was partitioned between H₂O andCH₂Cl₂, and the combined organic layers were washed with brine, driedover MgSO₄, filtered and concentrated in vacuo. The crude product waschromatographically purified using Teledyne Isco CombiFlash® system(normal phase: 4 g column, eluent: 3-5% CH₃OH/CH₂Cl₂). The titledcompound was obtained after concentration in vacuo over night as clearoil (29 mg, 44.0%). LC-MS (ESI+) m/z 385.2 [M+H]⁺; ¹H NMR (600 MHz,DMSO-d₆) δ ppm 12.75 (s, 1H), 10.97 (s, 1H), 7.75 (d, J=8.67 Hz, 1H),7.50 (dd, J=2.68, 8.77 Hz, 1H), 7.41-7.34 (m, 3H), 7.30 (dd, J=3.84,5.15 Hz, 1H), 5.28 (s, 2H), 5.08 (d, J=10.50 Hz, 1H), 4.20-4.14 (m, 1H),3.96 (t, J=12.41 Hz, 1H), 3.51 (d, J=12.27 Hz, 1H), 3.42 (d, J=12.46 Hz,1H), 3.33 (s, 1H), 3.25 (s, 2H), 3.19 (s, 1H), 2.84 (t, J=7.45 Hz, 2H),2.74 (q, J=7.54 Hz, 2H), 1.17 (t, J=7.54 Hz, 3H).

Example 1-2{1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidin-2-yl}methanol

A mixture of INTERMEDIATE a1 (50 mg, 0.171 mmol), piperidin-2-ylmethanol(79 mg, 0.685 mmol), and N-ethyl-N-isopropylpropan-2-amine (44.2 mg,0.342 mmol) in ethanol (3 mL) was stirred at ambient temperature for 3d.

For work-up, the reaction mixture was extracted using H₂O/CH₂Cl₂, andthe combined organic layers were washed with brine, dried over MgSO₄,filtered and concentrated in vacuo. The crude product waschromatographically purified using Teledyne Isco CombiFlash® system(normal phase: 4 g column, eluent: 5-10% CH₃OH/CH₂Cl₂). The titledcompound was obtained after concentration in vacuo overnight as clearoil (13 mg, 20.48%). LC-MS (ESI+) m/z 371.2 [M+H]⁺; ¹H NMR (600 MHz,DMSO-d₆) δ ppm 7.38-7.29 (m, 4H), 6.16 (s, 1H), 6.07 (s, 1H), 5.09 (tt,J=7.0, 4.1 Hz, 1H), 4.65 (t, J=5.3 Hz, 1H), 4.05 (s, 2H), 3.76-3.67 (m,2H), 3.55 (ddd, J=11.3, 6.6, 5.0 Hz, 1H), 3.35-3.27 (m, 1H), 2.35 (s,3H), 1.81-1.69 (m, 3H), 1.68-1.56 (m, 3H).

Example 1-32-(4-chlorobenzyl)-5-methyl-N-(1-methylcyclopropyl)pyrazolo[1,5-a]pyrimidin-7-amine

A mixture of INTERMEDIATE a1 (50 mg, 0.171 mmol),1-methylcyclopropanamine (48.7 mg, 0.685 mmol), andN-ethyl-N-isopropylpropan-2-amine (44.2 mg, 0.342 mmol) in ethanol (3mL) were stirred at ambient temperature for 3 d.

For work-up, the reaction mixture was extracted using H₂O/CH₂Cl₂ and thecombined organic layers were washed with brine, dried over MgSO₄,filtered and concentrated in vacuo. The crude product was purifiedchromatographically using a Teledyne Isco CombiFlash® system (normalphase: 4 g column, eluent: 3-5% CH₃OH/CH₂Cl₂). The titled compound wasobtained after concentration in vacuo over night as clear oil (22 mg,39.3%). LC-MS (ESI+) m/z 327.2 [M+H]⁺; ¹H NMR (600 MHz, DMSO-d₆) δ ppm8.07 (s, 1H), 7.37-7.27 (m, 4H), 6.11 (s, 1H), 6.03 (s, 1H), 4.05 (s,2H), 2.38 (s, 3H), 1.38 (s, 3H), 0.90-0.84 (m, 2H), 0.79-0.74 (m, 2H).

Example 1-42-(4-chlorobenzyl)-7-(3,3-difluoropiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine

A mixture of INTERMEDIATE a1 (50 mg, 0.171 mmol), 3,3-difluoropiperidinehydrochloride (108 mg, 0.685 mmol), andN-ethyl-N-isopropylpropan-2-amine (133 mg, 1.027 mmol) in ethanol (3 mL)was stirred at ambient temperature for 3 d.

For work-up, the reaction mixture was extracted using H₂O/CH₂Cl₂, andthe combined organic layers were washed with brine, dried over MgSO₄,filtered and concentrated in vacuo. The crude product was purifiedchromatographically using a Teledyne Isco CombiFlash® system (normalphase: 4 g column, eluent: 5-10% CH₃OH/CH₂Cl₂). The obtained materialwas triturated with a small amount of ethyl acetate, and the solid wascollected by filtration. The titled compound was obtained as white solidafter drying in vacuo overnight (44 mg, 68.2%). LC-MS (ESI+) m/z 377.2[M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.38-7.29 (m, 4H), 6.33 (s, 1H),6.17 (s, 1H), 4.29 (t, J=11.91 Hz, 2H), 4.08 (s, 2H), 3.69 (t, J=5.32Hz, 2H), 2.40 (s, 3H), 2.15 (tt, J=6.28, 13.85 Hz, 2H), 1.90 (dq,J=5.43, 6.02, 11.50 Hz, 2H).

Example 1-51-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]-3,3-difluoropiperidin-4-ol

The synthesis was done analogously to the synthesis described in EXAMPLE1-4 to obtain the titled compound as a white solid (15 mg, 22.31%).LC-MS (ESI+) m/z 393.2 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.38-7.29(m, 4H), 6.34 (s, 1H), 6.17 (s, 1H), 5.80 (d, J=4.8 Hz, 1H), 4.49 (ddd,J=18.7, 13.8, 5.4 Hz, 1H), 4.09 (s, 3H), 3.96 (t, J=10.3 Hz, 1H), 3.82(td, J=8.4, 6.8, 4.2 Hz, 1H), 3.59 (ddd, J=12.2, 8.1, 3.2 Hz, 1H), 2.40(s, 3H), 2.03 (ddt, J=15.2, 7.4, 3.8 Hz, 1H), 1.85 (dtt, J=16.6, 7.5,3.2 Hz, 1H).

Example 1-6(3S)-1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidin-3-ol

7-Chloro-2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidine (100 mg,0.342 mmol) was added to a suspension of sodium carbonate (72.6 mg,0.685 mmol) and (S)-piperidin-3-ol (45.0 mg, 0.445 mmol) inN,N-dimethylformamide (5 mL). The mixture was stirred at 65° C. for 3hours. The reaction mixture was partitioned between water and ethylacetate, the organic layer was separated, and the aqueous layer wasextracted with ethyl acetate. The combined organic layers were washedwith water, dried over sodium sulfate, and concentrated. The residue waspurified by flash chromatography, C18 column (acetonitrile/water 3:1v/v) to provide the titled compound (48.3 mg, 39.5%). MS(ESI+) m/z 357.1[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.44 (m, 1H), 1.58 (m, 1H), 1.82(m, 1H), 1.94 (m, 1H), 2.37 (s, 3H), 3.09 (m, 1H), 3.17 (m, 1H), 3.68(m, 1H), 4.03 (m, 1H), 4.06 (s, 2H), 4.15 (m, 1H), 6.11 (s, 1H), 6.20(s, 1H), 7.32 (m, 4H).

Example 1-7(3R)-1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidin-3-ol

7-Chloro-2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidine (70 mg,0.240 mmol) was added to a suspension of potassium carbonate (33.1 mg,0.240 mmol) and (R)-piperidin-3-ol (26.7 mg, 0.264 mmol) inN,N-dimethylformamide (6 mL). The mixture was stirred at 50° C.overnight. The reaction mixture was partitioned between water and ethylacetate, the organic layer was separated, and the aqueous layer wasextracted with ethyl acetate. The combined organic layers were washedwith water, dried over sodium sulfate, and concentrated. Purification ofthe residue by preparative-HPLC (column: XBridge® C18, 19×150 mm, 5 μm;mobile phase A: water/10 mM NH₄HCO₃, mobile phase B: acetonitrile; flowrate: 20 mL/minute; gradient: 30% B to 70% B in 10 minutes; 254 nm)provided the titled compound (28.5 mg, 33.3%). MS(ESI+) m/z 357.1[M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 1.71 (m, 2H), 2.05 (m, 2H), 2.47(s, 3H), 3.34 (m, 2H), 3.95 (m, 2H), 4.13 (s, 2H), 4.23 (m, 1H), 6.13(s, 1H), 6.22 (s, 1H), 7.32 (m, 4H).

Example 1-8{(3S)-1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidin-3-yl}methanol

7-Chloro-2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidine (70 mg,0.240 mmol) was added to a suspension of potassium carbonate (33.1 mg,0.240 mmol) and (S)-piperidin-3-ylmethanol (30.4 mg, 0.264 mmol) inN,N-dimethylformamide (6 mL). The mixture was stirred at 50° C.overnight. The reaction mixture was partitioned between water and ethylacetate, the organic layer was separated, and the aqueous layer wasextracted with ethyl acetate. The combined organic layers were washedwith water, dried over sodium sulfate, and concentrated. Purification ofthe residue by preparative-HPLC (column: Waters XBridge® C18, 19×150 mm,5 μm; mobile phase A: water/0.05% trifluoroacetic acid, mobile phase B:acetonitrile; flow rate: 20 mL/minute; gradient: 30% B to 70% B in 10minutes; 254 nm) provided the titled compound as a trifluoroacetic acidsalt (21.6 mg, 18.6%). MS(ESI+) m/z 371.1 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.25 (m, 1H), 1.72 (m, 4H), 2.38 (s, 3H), 2.97 (m, 2H),3.37 (m, 2H), 4.05 (s, 2H), 4.22 (m, 1H), 4.29 (m, 1H), 4.64 (t, 1H),6.12 (s, 1H), 6.19 (s, 1H), 7.33 (m, 4H).

Example 1-92-(4-chlorobenzyl)-5-methyl-7-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidine

Into a mixture of piperidine (17.49 mg, 0.205 mmol) and potassiumcarbonate (71 mg, 0.513 mmol) in 1,4-dioxane (5 mL) was added7-chloro-2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidine (50 mg,0.171 mmol). The resulting mixture was stirred overnight at 95° C. Afterconcentration under vacuum, the residue was purified bypreparative-HPLC, Column: Waters XBridge® C18, 19×150 mm, 5 μm; MobilePhase A: water/0.05% trifluoroacetic acid, Mobile Phase B: acetonitrile;Flow rate: 20 mL/minute; Gradient: 30% B to 70% B in 10 minutes; 254 nm,to provide the titled compound as a trifluoroacetic acid salt (33.7 mg,43.3%). MS (ESI+) m/z 341.1 [M+H]⁺; NMR (400 MHz, CD₃OD) δ ppm 1.82 (m,6H), 2.51 (s, 3H), 4.11 (s, 2H), 4.23 (m, 4H), 6.21 (s, 1H), 6.42 (s,1H), 7.29 (m, 4H).

Example 1-101-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidin-2-one

7-Chloro-2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidine (100 mg,0.342 mmol) was added to a suspension of piperidin-2-one (67.9 mg, 0.685mmol), tris(dibenzylideneacetone)dipalladium(0) (Pd₂(dba)₃, 31 mg, 0.034mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos, 16mg, 0.034 mmol) and cesium carbonate (335 mg, 1.027 mmol) in 1,4-dioxane(3 mL). The vessel was flushed with argon, and then the mixture wasstirred and heated in the microwave (100° C., 300 W, 1 hour). The finalmixture was concentrated under vacuum. Purification of the residue byflash chromatography on silica eluted with ethyl acetate/petroleum ether(gradient ethyl acetate:petroleum ether from 0:1 to 1:1) provided thetitled compound (42.1 mg, 34.7%). MS(ESI+) m/z 355.1 [M+H]⁺; ¹H NMR (400MHz, CD₃OD) δ ppm 2.07 (m, 4H), 2.60 (s, 3H), 2.65 (t, 2H), 3.82 (t,2H), 4.16 (s, 2H), 6.38 (s, 1H), 6.93 (s, 1H), 7.31 (m, 4H).

Example 1-11N-{(3R)-1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]pyrrolidin-3-yl}acetamide

Into a mixture of N-[(3R)-pyrrolidin-3-yl]acetamide (32.9 mg, 0.257mmol) and potassium carbonate (71 mg, 0.513 mmol) in 1,4-dioxane (5 mL)was added 7-chloro-2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidine(50 mg, 0.171 mmol). The resulting mixture was stirred overnight at 95°C. Water and ethyl acetate were added, the organic layer was separatedand the aqueous layer was extracted with ethyl acetate. The combinedorganic layers were washed with water and dried over sodium sulfate.After filtration and concentration under reduced pressure, the cruderesidue was purified by preparative-HPLC, Column: Waters XBridge® C18,19×150 mm, 5 μm; Mobile Phase A: water/0.1% trifluoroacetic acid, MobilePhase B: acetonitrile; Flow rate: 20 mL/minute; Gradient: 30% B to 70% Bin 10 minutes; 254 nm, to provide the titled compound (45 mg, 68.5%). MS(ESI+) m/z 384.1 [M+H]⁺; NMR (400 MHz, DMSO-d₆) δ ppm 1.81 (s, 3H), 1.90(m, 1H), 2.11 (m, 1H), 2.29 (s, 3H), 3.85 (m, 3H), 4.00 (s, 2H), 4.10(m, 1H), 4.32 (m, 1H), 5.80 (s, 1H), 5.98 (s, 1H), 7.33 (m, 4H), 8.17(d, 1H).

Example 1-122-(4-chlorobenzyl)-5-methyl-7-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine

Into a mixture of pyrrolidine (18.26 mg, 0.257 mmol) and potassiumcarbonate (71 mg, 0.513 mmol) in 1,4-dioxane (5 mL) was added7-chloro-2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidine (50 mg,0.171 mmol). The resulting mixture was stirred overnight at 95° C. Waterand ethyl acetate were added, the organic layer was separated, and theaqueous layer was extracted with ethyl acetate. The combined organiclayers were washed with water and dried over sodium sulfate. Afterfiltration and concentration under reduced pressure, the crude productwas purified by preparative-HPLC, Column: Waters XBridge® C18, 19×150mm, 5 μm; Mobile Phase A: water/0.1% trifluoroacetic acid, Mobile PhaseB: acetonitrile; Flow rate: 20 mL/minute; Gradient: 30% B to 70% B in 10minutes; 254 nm, to give the titled compound (41.3 mg, 73.8%). MS (ESI+)m/z 327.3 [M+H]⁺; NMR (400 MHz, CD₃OD) δ ppm 2.10 (m, 4H), 2.50 (s, 3H),3.82 (m, 2H), 4.11 (s, 2H), 4.64 (m, 2H), 6.14 (s, 1H), 6.15 (s, 1H),7.32 (m, 4H).

Example 1-137-(azetidin-1-yl)-2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidine

7-Chloro-2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidine (50 mg,0.171 mmol) was added to a solution of azetidine (14.66 mg, 0.257 mmol)and triethylamine (52.0 mg, 0.513 mmol) in acetonitrile (5 mL). Theresulting mixture was stirred overnight at 95° C. Water and ethylacetate were added, the organic layer was separated and the aqueouslayer was extracted with ethyl acetate. The combined organic layers werewashed with water and dried over sodium sulfate. After filtration andconcentration under reduced pressure, the crude product was purified bypreparative-HPLC, Column: Waters XBridge® C18, 19×150 mm, 5 μm; MobilePhase A: water/0.1% trifluoroacetic acid, Mobile Phase B: acetonitrile;Flow rate: 20 mL/minute; Gradient: 30% B to 70% B in 10 minutes; 254 nm,to provide the titled compound (42.5 mg, 79.4%). MS (ESI+) m/z 313.3[M+H]⁺; NMR (400 MHz, CD₃OD) δ ppm 2.48 (s, 3H), 2.61 (m, 2H), 4.09 (s,2H), 4.51 (m, 2H), 5.15 (m, 2H), 5.88 (s, 1H), 6.12 (s, 1H), 7.32 (m,4H).

Example 1-14N-tert-butyl-2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-amine

7-Chloro-2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidine (50 mg,0.171 mmol) was added to a solution of 2-methylpropan-2-amine (62.6 mg,0.856 mmol) and triethylamine (52.0 mg, 0.513 mmol) in acetonitrile (5mL). The mixture was stirred at 95° C. overnight and then concentratedunder vacuum. The residue was purified by preparative-HPLC (column:Waters XBridge® C18, 19×150 mm, 5 μm; mobile phase A: water/0.05%trifluoroacetic acid, mobile phase B: acetonitrile; flow rate: 20mL/minute; gradient: 30% B to 70% B in 10 minutes; 254 nm) to providethe titled compound (5.1 mg, 9.1%). MS(ESI+) m/z 329.2 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.57 (s, 9H), 2.41 (s, 3H), 4.10 (s, 2H), 4.60(brs, 1H), 6.06 (s, 1H), 6.20 (s, 1H), 7.31 (m, 4H).

Example 1-152-(4-chlorobenzyl)-5-methyl-N-[1-(trifluoromethyl)cyclopropyl]pyrazolo[1,5-a]pyrimidin-7-amine

7-Chloro-2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidine (100 mg,0.342 mmol) was added to a suspension of1-(trifluoromethyl)cyclopropanamine hydrochloride (276 mg, 1.711 mmol),cesium carbonate (335 mg, 1.027 mmol) and potassium iodide (56.8 mg,0.342 mmol) in 1,4-dioxane (5 mL). The resulting mixture was stirred at135° C. overnight. This reaction mixture was concentrated under vacuum,and the residue was purified by preparative-HPLC (column: WatersXBridge® C18, 19×150 mm, 5 m; mobile phase A: water/0.5% NH₄HCO₃, mobilephase B: acetonitrile; flow rate: 20 mL/minute; gradient: 30% B to 70% Bin 10 minutes; 254 nm) to provide the titled compound (38.3 mg, 29.4%).MS(ESI+) m/z 381.2 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 1.36 (m, 2H),1.56 (m, 2H), 2.48 (s, 3H), 4.13 (s, 2H), 6.10 (s, 1H), 6.27 (s, 1H),7.30 (m, 4H).

Example 1-162-(4-chlorobenzyl)-5-methyl-N-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyrimidin-7-amine

7-Chloro-2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidine (20 mg,0.068 mmol) was added to a solution of 2,2,2-trifluoroethanamine (67.8mg, 0.685 mmol) and triethylamine (20.8 mg, 0.205 mmol) in acetonitrile(5 mL). The resulting mixture was stirred at 90° C. overnight. Thisreaction mixture was concentrated under vacuum, and the crude residuewas purified by preparative-HPLC (column: Waters XBridge® C18, 19×150mm, 5 μm; mobile phase A: water/0.05% trifluoroacetic acid, mobile phaseB: acetonitrile; flow rate: 20 mL/minute; gradient: 30% B to 70% B in 10minutes; 254 nm) to provide the titled compound as a trifluoroaceticacid salt (14.1 mg, 43.9%). MS(ESI+) m/z 355.3 [M+H]⁺; ¹H NMR (400 MHz,CD₃OD) δ ppm 2.63 (s, 3H), 4.21 (s, 2H), 4.43 (q, 2H), 6.32 (s, 1H),6.65 (s, 1H), 7.33 (m, 4H).

Example 1-17N-{(3S)-1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]pyrrolidin-3-yl}acetamide

Into a mixture of N-[(3S)-pyrrolidin-3-yl]acetamide (32.9 mg, 0.257mmol) and potassium carbonate (71 mg, 0.513 mmol) in 1,4-dioxane (5 mL)was added 7-chloro-2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidine(50 mg, 0.171 mmol). The resulting mixture was stirred overnight at 95°C. Water and ethyl acetate were added, the organic layer was separated,and the aqueous layer was extracted with ethyl acetate. The combinedorganic layers were washed with water and dried over sodium sulfate.After filtration and concentration under reduced pressure, the crudeproduct was purified by preparative-HPLC, Column: Waters XBridge® C18,19×150 mm, 5 μm; Mobile Phase A: water/0.1% trifluoroacetic acid, MobilePhase B: acetonitrile; Flow rate: 20 mL/minute; Gradient: 30% B to 70% Bin 10 minutes; 254 nm, to provide the titled compound (56.7 mg, 86.4%).MS (ESI+) m/z 384.1 [M+H]⁺; NMR (400 MHz, DMSO-d₆) δ ppm 1.81 (s, 3H),1.90 (m, 1H), 2.11 (m, 1H), 2.29 (s, 3H), 3.85 (m, 3H), 4.00 (s, 2H),4.10 (m, 1H), 4.32 (m, 1H), 5.80 (s, 1H), 5.98 (s, 1H), 7.33 (m, 4H),8.17 (d, 1H).

Example 1-182-(4-chlorobenzyl)-5-methyl-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyrazolo[1,5-a]pyrimidin-7-amine

7-Chloro-2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidine (100 mg,0.342 mmol) was added to a suspension of(S)-1,1,1-trifluoropropan-2-amine hydrochloride (256 mg, 1.711 mmol),potassium iodide (85 mg, 0.513 mmol) and cesium carbonate (335 mg, 1.027mmol) in 1,4-dioxane (5 mL). The resulting solution was stirred at 130°C. for 48 hours. This reaction mixture was concentrated under vacuum,and the residue was purified by preparative-HPLC (column: WatersXBridge® C18, 19×150 mm, 5 μm; mobile phase A: water/0.1% NH₄HCO₃,mobile phase B: acetonitrile; flow rate: 20 mL/minute; gradient: 30% Bto 70% B in 10 minutes; 254 nm) to provide the titled compound (50.4 mg,39.9%). MS(ESI+) m/z 369.3 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 1.58(d, 3H), 2.47 (s, 3H), 4.13 (s, 2H), 4.68 (m, 1H), 6.11 (s, 1H), 6.26(s, 1H), 7.31 (m, 4H).

Example 1-191-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidine-3-carboxamide

7-Chloro-2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidine (100 mg,0.342 mmol) was added to a suspension of piperidine-3-carboxamide (65.8mg, 0.513 mmol) and potassium carbonate (95 mg, 0.685 mmol) inN,N-dimethylformamide (3 mL). The mixture was stirred at 50° C. for 5hours and then concentrated under vacuum. Purification of the residue byflash chromatography on silica gel eluted with methanol/dichloromethane(gradient methanol:dichloromethane from 0:1 to 1:3) provided a solid.Then washing the solid with ether provided the titled compound (114.9mg, 87%). MS(ESI+) m/z 384.1 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 1.83(m, 1H), 1.96 (m, 2H), 2.14 (m, 1H), 2.55 (s, 3H), 2.77 (m, 1H), 3.32(m, 2H), 3.70 (m, 1H), 4.02 (m, 1H), 4.14 (s, 2H), 6.26 (s, 1H), 6.51(s, 1H), 7.31 (m, 4H).

Example 1-202-(4-chlorobenzyl)-5-methyl-N-[(2R)-1,1,1-trifluoropropan-2-yl]pyrazolo[1,5-a]pyrimidin-7-amine

7-Chloro-2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidine (100 mg,0.342 mmol) was added to a suspension of(R)-1,1,1-trifluoropropan-2-amine hydrochloride (256 mg, 1.711 mmol),potassium iodide (114 mg, 0.685 mmol) and cesium carbonate (335 mg,1.027 mmol) in 1,4-dioxane (5 mL). The resulting solution was stirred at130° C. for 48 hours. This reaction mixture was concentrated undervacuum, and the residue was purified by preparative-HPLC (column: WatersXBridge® C18, 19×150 mm, 5 μm; mobile phase A: water/0.1% NH₄HCO₃,mobile phase B: acetonitrile; flow rate: 20 mL/minute; gradient: 30% Bto 70% B in 10 minutes; 254 nm) to provide the titled compound (35.9 mg,28.4%). MS(ESI+) m/z 369.3 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 1.57(d, 3H), 2.46 (s, 3H), 4.11 (s, 2H), 4.67 (m, 1H), 6.11 (s, 1H), 6.25(s, 1H), 7.28 (m, 4H).

Example 1-21{(3R)-1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidin-3-yl}methanol

7-Chloro-2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidine (100 mg,0.342 mmol) was added to a suspension of (R)-piperidin-3-ylmethanol(59.1 mg, 0.513 mmol) and potassium carbonate (95 mg, 0.685 mmol) inN,N-dimethylformamide (3 mL). The mixture was stirred at 60° C. for 5hours and then concentrated under vacuum. Purification of the residue byflash chromatography on silica gel eluted with ethyl acetate/petroleumether (gradient ethyl acetate:petroleum ether from 0:1 to 1:1) providedthe titled compound (44.4 mg, 35%). MS(ESI+) m/z 371.1 [M+H]⁺; ¹H NMR(400 MHz, CD₃OD) δ ppm 1.32 (m, 1H), 1.66 (m, 1H), 1.74 (m, 2H), 1.88(m, 1H), 2.34 (s, 3H), 3.04 (m, 1H), 3.17 (m, 1H), 3.45 (m, 1H), 3.54(m, 1H), 4.04 (m, 4H), 6.02 (s, 1H), 6.09 (s, 1H), 7.18 (m, 4H).

Preparation of Compounds Derived from Intermediate a2 Example 2-12-(1-{2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}piperidin-2-yl)ethanol

A mixture of INTERMEDIATE a2 (300 mg, 0.980 mmol),2-(piperidin-2-yl)ethanol (506 mg, 3.92 mmol), andN-ethyl-N-isopropylpropan-2-amine (253 mg, 1.960 mmol) was dissolved inethanol (3 mL) and stirred at 50° C. for 12 h.

For work-up, the reaction mixture was extracted with H₂O/CH₂Cl₂, and theorganic layers were washed with brine, dried over MgSO₄, filtered andconcentrated. The residue was purified chromatographically using aTeledyne Isco CombiFlash® system (normal phase: 4 g column, eluent: 3-5%CH₃OH/CH₂Cl₂) to give the titled compound as a clear yellow oil (115 mg,29.4%).

Example 2-22-[1-(4-chlorophenyl)ethyl]-5-methyl-N-(1-methylcyclopropyl)pyrazolo[1,5-a]pyrimidin-7-amine

The synthesis was done analogously to the synthesis described in EXAMPLE2-1 to obtain the titled compound as a clear oil (7.49%). LC-MS (ESI+)m/z 341.2 [M+H]⁺; ¹H NMR (600 MHz, CDCl₃) δ ppm 7.29-7.19 (m, 4H), 6.64(s, 1H), 6.24 (s, 1H), 6.07 (s, 1H), 4.25 (q, J=7.2 Hz, 1H), 2.55 (s,3H), 1.67 (d, J=7.3 Hz, 3H), 1.49 (s, 3H), 1.02-0.97 (m, 2H), 0.87-0.81(m, 2H).

Example 2-32-[1-(4-chlorophenyl)ethyl]-7-(3,3-difluoropyrrolidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine

The synthesis was done analogously to the synthesis described in EXAMPLE2-1 to obtain the titled compound as a clear oil (13.54%). LC-MS (ESI+)m/z 377.2 [M+H]⁺; ¹H NMR (600 MHz, DMSO-d₆) δ ppm 7.34 (s, 7H), 6.10 (s,2H), 5.95 (s, 2H), 5.76 (s, 1H), 4.39 (t, J=13.2 Hz, 5H), 4.27 (q, J=7.2Hz, 2H), 2.34 (s, 6H), 1.61 (d, J=7.2 Hz, 7H).

Example 2-42-[1-(4-chlorophenyl)ethyl]-7-(4-fluoropiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine

A mixture of INTERMEDIATE a2 (70 mg, 0.229 mmol), 4-fluoropiperidinehydrochloride (96 mg, 0.686 mmol), and N-ethyl-N-isopropylpropan-2-amine(117 mg, 1.372 mmol) was dissolved in dioxane (2 mL) and stirred at 50°C. for 6 h and then stirred overnight at room temperature.

For work-up, the reaction mixture was extracted with H₂O/ethyl acetate,and the combined organic layers were washed with brine, dried overMgSO₄, filtered and concentrated. After chromatographic purificationusing a Teledyne Isco CombiFlash® system (normal phase: 4 g column,eluent: CH₃OH/CH₂Cl₂), the titled compound was obtained as clear oil (54mg, 63.3%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.34 (s, 6H), 6.25 (s, 2H),6.19 (s, 2H), 4.99 (tt, J=6.8, 3.4 Hz, 1H), 4.31 (q, J=7.2 Hz, 2H), 3.78(t, J=10.2 Hz, 4H), 3.70 (dq, J=11.2, 5.0 Hz, 4H), 3.29 (s, 3H), 2.39(s, 6H), 2.05 (dddd, J=26.0, 12.4, 8.4, 3.9 Hz, 4H), 1.86 (dtd, J=13.6,10.5, 6.4 Hz, 4H), 1.62 (d, J=7.1 Hz, 6H).

Example 2-5(1-{2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}piperidin-2-yl)methanol

A mixture of INTERMEDIATE a2 (70 mg, 0.229 mmol), piperidin-2-ylmethanol(79 mg, 0.686 mmol), and N-ethyl-N-isopropylpropan-2-amine (89 mg, 0.686mmol) was dissolved in dioxane (3 mL) and stirred at 50° C. for 6 h andstirred over night at room temperature. The reaction was then placed ina CEM-MW microwave reactor at 140° C. for 90 minutes.

For work-up, the reaction mixture was extracted with H₂O/ethyl acetateand the organic layers were washed with brine, dried over MgSO₄,filtered and concentrated. After chromatographic purification using aTeledyne Isco CombiFlash® system (normal phase: 4 g column, eluent:CH₃OH/CH₂Cl₂), the titled compound was obtained as a clear oil (64 mg,72.2%). LC-MS (ESI+) m/z 385.2 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm7.39-7.30 (m, 4H), 6.17-6.07 (m, 2H), 5.03 (s, 1H), 4.65 (td, J=5.1, 3.6Hz, 2H), 4.32-4.24 (m, 2H), 3.81-3.68 (m, 4H), 3.57 (dt, J=11.3, 5.8 Hz,2H), 3.34-3.25 (m, 2H), 2.35 (d, J=1.0 Hz, 3H), 1.74 (d, J=18.8 Hz, 3H).

Example 2-62-[1-(4-chlorophenyl)ethyl]-7-(3-fluoropiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine

The synthesis was done analogously to the synthesis described in EXAMPLE2-4 to obtain the titled compound as a clear oil (66.9%). LC-MS (ESI+)m/z 373.2 [M+H]⁺; ¹H NMR (600 MHz, DMSO-d₆) δ ppm 7.34 (d, J=2.1 Hz,8H), 6.25 (s, 2H), 6.18 (d, J=8.5 Hz, 2H), 4.90 (dh, J=6.0, 2.9 Hz, 1H),4.82 (tq, J=5.7, 2.8 Hz, 1H), 4.34-4.19 (m, 2H), 3.87-3.77 (m, 4H), 3.47(ddt, J=12.1, 9.1, 4.5 Hz, 2H), 3.32 (s, 1H), 2.38 (s, 3H), 2.03-1.85(m, 3H), 1.67-1.60 (m, 4H).

Example 2-72-[1-(4-chlorophenyl)ethyl]-7-(3,3-difluoropiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine

The synthesis was done analogously to the synthesis described in EXAMPLE2-4 to obtain the titled compound as a clear oil (66.0%). LC-MS (ESI+)m/z 391.2; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.34 (s, 4H), 6.32 (s, 1H),6.21 (s, 1H), 4.39-4.20 (m, 2H), 3.68 (t, J=5.6 Hz, 2H), 2.40 (s, 3H),2.14 (tt, J=13.9, 6.3 Hz, 2H), 1.90 (d, J=5.9 Hz, 2H), 1.63 (d, J=7.3Hz, 4H).

Example 2-8N-tert-butyl-2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-amine

A mixture of INTERMEDIATE a2 (80 mg, 0.261 mmol), 2-methylpropan-2-amine(57.3 mg, 0.784 mmol), and N-ethyl-N-isopropylpropan-2-amine (101 mg,0.784 mmol) was dissolved in dioxane (2 mL) and irradiated in a CEMmicrowave reactor at 160° C. for 120 minutes.

For work-up, the reaction mixture was extracted with ethyl acetate andthe organic layers were washed with brine, dried over MgSO₄, filtered,and concentrated. Chromatographic purification with Teledyne IscoCombiFlash® system (normal phase: 4 g column, eluent: 3-5% CH₃OH/CH₂Cl₂)gave the titled compound as an orange oil (15 mg, 16.74%). LC-MS (ESI+)m/z 343.2 [M+H]⁺; ¹H NMR (600 MHz, DMSO-d₆) δ ppm 7.34 (s, 3H), 6.42 (s,1H), 6.20 (s, 1H), 6.15 (s, 1H), 4.29 (q, J=7.2 Hz, 1H), 2.38 (s, 3H),1.60 (d, J=7.2 Hz, 3H), 1.48 (s, 9H).

Example 2-92-[1-(4-chlorophenyl)ethyl]-5-methyl-7-(2-oxa-7-azaspiro[3.5]non-7-yl)pyrazolo[1,5-a]pyrimidine

The synthesis was done analogously to the synthesis described in EXAMPLE2-4 to obtain the titled compound as a clear oil (24.24%). LC-MS (ESI+)m/z 397.2 [M+H]⁺; ¹H NMR (600 MHz, DMSO-d₆) δ ppm 7.34 (s, 5H), 6.19 (d,J=13.8 Hz, 3H), 4.37 (s, 7H), 4.30 (q, J=7.2 Hz, 2H), 3.64-3.56 (m, 7H),2.37 (s, 5H), 1.99 (s, 1H), 1.95 (t, J=5.6 Hz, 7H), 1.62 (d, J=7.2 Hz,5H), 1.17 (t, J=7.1 Hz, 1H).

Example 2-10(3S)-1-{2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}piperidin-3-ol

The synthesis was done analogously to the synthesis described in EXAMPLE2-4 to obtain the titled compound as a clear oil (61.3%). LC-MS (ESI+)m/z 371.2 [M+H]⁺; ¹H NMR (600 MHz, DMSO-d₆) δ ppm 7.35 (d, J=2.1 Hz,3H), 6.21-6.14 (m, 2H), 4.93 (d, J=4.3 Hz, 1H), 4.29 (q, J=7.2 Hz, 1H),4.15 (dt, J=12.7, 3.4 Hz, 1H), 4.09-3.99 (m, 1H), 3.69 (dd, J=8.5, 4.2Hz, 1H), 3.20-3.04 (m, 2H), 2.37 (s, 3H), 2.01-1.90 (m, 1H), 1.83 (dp,J=12.8, 4.2 Hz, 1H), 1.64-1.52 (m, 4H), 1.49-1.40 (m, 1H).

Example 2-11(3R)-1-{2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}piperidin-3-ol

The synthesis was done analogously to the synthesis described in EXAMPLE2-4 to obtain the titled compound as a clear oil (68.4%). LC-MS (ESI+)m/z 371.2 [M+H]⁺; ¹H NMR (600 MHz, DMSO-d₆) δ ppm 7.38-7.31 (m, 4H),6.21-6.14 (m, 2H), 4.94 (d, J=4.3 Hz, 1H), 4.29 (q, J=7.2 Hz, 1H), 4.15(dt, J=12.4, 3.3 Hz, 1H), 4.09-3.99 (m, 2H), 3.68 (tp, J=8.3, 4.1 Hz,1H), 3.35-3.26 (m, 1H), 3.20-3.04 (m, 2H), 2.37 (s, 3H), 1.99 (s, 1H),1.94 (dq, J=12.6, 4.3 Hz, 1H), 1.83 (dp, J=12.9, 4.4 Hz, 1H), 1.64-1.53(m, 4H), 1.44 (dddd, J=12.7, 10.6, 8.9, 4.0 Hz, 1H), 1.17 (t, J=7.1 Hz,1H).

Example 2-127-(azetidin-1-yl)-2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidine

The synthesis was done analogously to the synthesis described in EXAMPLE2-5 to obtain the titled compound as a white solid (28.1%). LC-MS (ESI+)m/z 372.2 [M+H]⁺; ¹H NMR (600 MHz, DMSO-d₆) δ ppm 7.33 (d, J=0.7 Hz,4H), 5.99 (s, 1H), 5.61 (s, 1H), 4.43-4.37 (m, 4H), 4.22 (q, J=7.2 Hz,1H), 2.41-2.32 (m, 2H), 2.29 (s, 3H), 1.58 (d, J=7.2 Hz, 3H).

Example 2-132-[1-(4-chlorophenyl)ethyl]-5-methyl-7-(7-oxa-2-azaspiro[3.5]non-2-yl)pyrazolo[1,5-a]pyrimidine

The synthesis was done analogously to the synthesis described in EXAMPLE2-5 to obtain the titled compound as a white solid (62.8%). LC-MS (ESI+)m/z 398.1 [M+H]⁺; ¹H NMR (600 MHz, DMSO-d₆) δ ppm 7.37-7.29 (m, 4H),6.01 (s, 1H), 5.65 (s, 1H), 4.23 (q, J=7.2 Hz, 1H), 4.17 (s, 5H), 3.55(q, J=6.4, 5.5 Hz, 4H), 3.33 (d, J=8.7 Hz, 2H), 2.29 (s, 3H), 1.78 (t,J=5.3 Hz, 4H), 1.59 (d, J=7.2 Hz, 3H).

Example 2-142-[1-(4-chlorophenyl)ethyl]-N-(3-fluorocyclobutyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-amine

The synthesis was done analogously to the synthesis described in EXAMPLE2-5 to obtain the titled compound as a clear oil (68.30%). LC-MS (ESI+)m/z 360.1

Example 2-15(2R,3R)-1-{2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}-3-ethylazetidine-2-carboxylicacid

The synthesis was done analogously to the synthesis described in EXAMPLE2-4 to obtain the titled compound as a clear foam (17.55%). LC-MS (ESI+)m/z 399.1 [M+H]⁺; ¹H NMR (600 MHz, DMSO-d₆) δ ppm 12.81 (s, 1H),7.35-7.26 (m, 4H), 5.93 (d, J=10.1 Hz, 1H), 5.74 (d, J=28.4 Hz, 1H),5.52 (s, 1H), 4.33 (s, 1H), 4.18 (q, J=7.2 Hz, 1H), 4.13 (s, 1H), 3.78(s, 1H), 3.40-3.35 (m, 1H), 3.32 (d, J=6.1 Hz, 1H), 3.11 (s, 1H), 2.31(d, J=1.8 Hz, 3H), 1.60-1.53 (m, 4H), 1.44 (dq, J=14.7, 7.6 Hz, 1H),1.21-1.16 (m, 2H), 0.94 (t, J=7.3 Hz, 1H), 0.87 (td, J=7.4, 2.4 Hz, 3H).

Example 2-162-[1-(4-chlorophenyl)ethyl]-N-[(3,3-difluorocyclobutyl)methyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-amine

The synthesis was done analogously to the synthesis described in EXAMPLE2-5 to obtain the titled compound as a clear oil (71.6%). LC-MS (ESI+)m/z 392.1 [M+H]⁺; ¹H NMR (600 MHz, DMSO-d₆) δ ppm 7.85 (t, J=6.3 Hz,2H), 7.33 (d, J=0.7 Hz, 8H), 6.15 (s, 2H), 6.08 (s, 2H), 5.76 (s, 1H),4.29 (q, J=7.2 Hz, 2H), 3.50-3.40 (m, 4H), 3.32 (d, J=5.8 Hz, 1H),2.69-2.58 (m, 4H), 2.57-2.51 (m, 1H), 2.34 (s, 10H), 1.62 (d, J=7.2 Hz,6H), 1.04 (d, J=6.1 Hz, 1H).

Example 2-17N-[(3S)-1-{2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}pyrrolidin-3-yl]acetamide

7-Chloro-2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidine(100 mg, 0.327 mmol, INTERMEDIATE a2) was added to a suspension ofpotassium carbonate (90 mg, 0.653 mmol) and(S)—N-(pyrrolidin-3-yl)acetamide (50.2 mg, 0.392 mmol) inN,N-dimethylformamide (5 mL). The mixture was stirred at 65° C.overnight and then concentrated under vacuum. Purification of theresidue by flash chromatography on silica gel eluted with ethylacetate/petroleum ether (gradient ethyl acetate:petroleum ether from 0:1to 1:1) provided the titled compound (56.1 mg, 43.2%). MS(ESI+) m/z398.1 [M+H]⁺; ¹H NMR (DMSO-d₆) δ ppm 1.59 (d, 3H), 1.81 (s, 3H), 1.88(m, 1H), 2.12 (m, 1H), 2.29 (s, 3H), 3.83 (m, 3H), 4.07 (m, 1H), 4.23(q, 1H), 4.32 (m, 1H), 5.79 (s, 1H), 6.01 (s, 1H), 7.33 (m, 4H), 8.18(d, 1H).

Example 2-18cis-3-({2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}amino)cyclobutanol

The synthesis was done analogously to the synthesis described in EXAMPLE2-5 to obtain the titled compound as a clear oil (33.1%). LC-MS (ESI+)m/z 357.2 [M+H]⁺; ¹H NMR (600 MHz, DMSO-d₆) δ ppm 7.65 (d, J=6.6 Hz,1H), 7.34 (s, 5H), 6.13 (s, 1H), 5.89 (s, 1H), 5.76 (s, 2H), 5.14 (d,J=6.2 Hz, 1H), 4.30 (q, J=7.2 Hz, 1H), 3.93-3.83 (m, 1H), 3.64-3.54 (m,1H), 3.41-3.26 (m, 3H), 2.71 (dddd, J=12.6, 6.3, 3.7, 1.2 Hz, 2H), 2.33(s, 3H), 2.07-1.97 (m, 2H), 1.62 (d, J=7.2 Hz, 3H), 1.04 (d, J=6.1 Hz,1H).

Example 2-19trans-3-({2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}amino)cyclobutanol

The synthesis was done analogously to the synthesis described in EXAMPLE2-8 to obtain the titled compound as a clear foam (23.29%). LC-MS (ESI+)m/z 357.2 [M+H]⁺; ¹H NMR (600 MHz, DMSO-d₆) δ ppm 7.70 (d, J=6.1 Hz,1H), 7.34 (s, 3H), 6.15 (s, 1H), 5.78 (s, 1H), 5.12 (d, J=5.2 Hz, 1H),4.32 (dq, J=19.1, 7.1 Hz, 2H), 4.18-4.10 (m, 1H), 2.34 (s, 3H), 2.24(dddd, J=9.7, 7.0, 5.1, 1.7 Hz, 2H), 1.62 (d, J=7.2 Hz, 3H).

Example 2-206-{2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}-6-azaspiro[3.4]octan-1-ol

The synthesis was done analogously to the synthesis described in EXAMPLE2-8 to obtain the titled compound as a white solid (74.9%). LC-MS (ESI+)m/z 397.2 [M+H]⁺.

Example 2-212-(1-(4-chlorophenyl)ethyl)-N-(3,3-difluorocyclobutyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-amine

The synthesis was done analogously to the synthesis described in EXAMPLE2-8 to obtain the titled compound as a clear oil (86%). LC-MS (ESI+) m/z377.1 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.05 (d, J=6.6 Hz, 1H),7.34 (s, 4H), 6.17 (s, 1H), 6.03 (s, 1H), 4.31 (q, J=7.2 Hz, 1H), 4.08(p, J=7.1, 6.6 Hz, 1H), 3.60 (p, J=6.1 Hz, 1H), 3.14-2.88 (m, 4H), 2.35(s, 3H), 1.63 (d, J=7.3 Hz, 3H), 1.04 (d, J=6.1 Hz, 4H).

Example 2-222-[1-(4-chlorophenyl)ethyl]-7-[(2R)-2-ethylpiperidin-1-yl]-5-methylpyrazolo[1,5-a]pyrimidine

The synthesis was done analogously to the synthesis described in EXAMPLE2-8 to obtain the titled compound as a clear oil (20.56%). LC-MS (ESI+)m/z 383.2 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.34 (d, J=1.5 Hz,4H), 6.15-6.09 (m, 2H), 4.97 (s, 1H), 4.29 (qd, J=7.2, 2.4 Hz, 1H), 3.80(d, J=13.1 Hz, 1H), 3.33-3.22 (m, 3H), 2.36 (s, 3H), 1.76-1.57 (m, 11H),0.72 (dt, J=13.3, 7.4 Hz, 3H).

Example 2-23N-[(3R)-1-{2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}pyrrolidin-3-yl]acetamide

7-Chloro-2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidine(100 mg, 0.327 mmol, INTERMEDIATE a2) was added to a suspension ofpotassium carbonate (90 mg, 0.653 mmol) and(R)—N-(pyrrolidin-3-yl)acetamide (46.0 mg, 0.359 mmol) inN,N-dimethylformamide (5 mL). The mixture was stirred at 65° C.overnight and then concentrated under vacuum. Purification of theresidue by flash chromatography on silica gel eluted with ethylacetate/petroleum ether (gradient ethyl acetate:petroleum ether from 0:1to 1:1) provided the titled compound (37.7 mg, 29.0%). MS(ESI+) m/z398.1 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.59 (d, 3H), 1.81 (s,3H), 1.88 (m, 1H), 2.13 (m, 1H), 2.29 (s, 3H), 3.84 (m, 3H), 4.07 (m,1H), 4.24 (q, 1H), 4.33 (m, 1H), 5.78 (s, 1H), 6.01 (s, 1H), 7.33 (m,4H), 8.18 (d, 1H).

Preparation of Compounds Derived from Intermediate a3 Example 3-12-(1-{2-[1-(4-chlorophenyl)propyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}piperidin-2-yl)ethanol

The synthesis was done analogously to the synthesis described in EXAMPLE2-8 to obtain the titled compound as a white solid (34.9%). LC-MS (ESI+)m/z 413.2 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.41-7.30 (m, 4H),6.20 (dd, J=21.4, 3.0 Hz, 2H), 5.05-4.96 (m, 1H), 4.58 (q, J=5.3 Hz,1H), 3.98 (t, J=7.7 Hz, 2H), 3.43-3.32 (m, 2H), 3.31-3.19 (m, 2H), 2.49(s, 2H), 2.35 (s, 3H), 2.21-2.09 (m, 1H), 2.04-1.91 (m, 1H), 1.91-1.78(m, 2H), 1.78-1.58 (m, 6H), 0.84 (td, J=7.4, 2.8 Hz, 3H).

Example 3-22-[1-(4-chlorophenyl)propyl]-7-(3,3-difluoropiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine

The synthesis was done analogously to the synthesis described in EXAMPLE2-8 to obtain the titled compound as a clear oil (93%). LC-MS (ESI+) m/z405.2 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.40-7.30 (m, 7H), 6.31(s, 2H), 6.26 (s, 2H), 5.76 (s, 1H), 4.28 (t, J=11.9 Hz, 3H), 4.02 (t,J=7.7 Hz, 2H), 3.67 (t, J=5.3 Hz, 3H), 3.29 (s, 1H), 2.39 (s, 5H),2.22-2.08 (m, 5H), 2.04-1.86 (m, 5H), 0.85 (t, J=7.3 Hz, 5H).

Preparation of Compounds Derived from Intermediate a4 Example 4-12-(1-{2-[1-(4-chlorophenyl)-2-methylpropyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}piperidin-2-yl)ethanol

The synthesis was done analogously to the synthesis described in EXAMPLE2-8 to obtain the titled compound as a white solid (37.2%). LC-MS (ESI+)m/z 427.2 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.44 (dd, J=8.6, 2.4Hz, 2H), 7.32 (dd, J=8.5, 2.1 Hz, 2H), 6.27 (d, J=2.1 Hz, 1H), 6.21 (d,J=6.9 Hz, 1H), 5.01 (d, J=7.7 Hz, 1H), 4.60 (dt, J=18.4, 5.2 Hz, 1H),3.94 (dd, J=32.5, 12.9 Hz, 1H), 3.68 (d, J=10.0 Hz, 1H), 3.45-3.32 (m,2H), 3.32-3.20 (m, 1H), 2.46 (ddd, J=13.2, 6.5, 3.4 Hz, 1H), 2.35 (s,3H), 1.95-1.59 (m, 8H), 0.88 (dd, J=6.6, 1.9 Hz, 3H), 0.77 (d, J=6.6 Hz,3H).

Example 4-22-[1-(4-chlorophenyl)-2-methylpropyl]-7-(3,3-difluoropiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine

The synthesis was done analogously to the synthesis described in EXAMPLE2-8 to obtain the titled compound as a yellow clear oil (73.8%). LC-MS(ESI+) m/z 419.2 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.48-7.41 (m,2H), 7.36-7.29 (m, 2H), 6.35 (s, 1H), 6.31 (s, 1H), 4.31 (t, J=12.0 Hz,2H), 3.76-3.63 (m, 3H), 3.30 (d, J=8.5 Hz, 1H), 2.39 (s, 4H), 2.15 (tt,J=14.0, 6.3 Hz, 2H), 1.91 (p, J=5.7 Hz, 2H), 0.88 (d, J=6.4 Hz, 3H),0.78 (d, J=6.5 Hz, 3H).

Preparation of Compounds Derived from Intermediate a5 Example 5-12-(1-{2-[1-(4-chlorophenyl)butyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}piperidin-2-yl)ethanol

The synthesis was done analogously to the synthesis described in EXAMPLE2-8 to obtain the titled compound as a clear oil (75%). LC-MS (ESI+) m/z427.2 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.41-7.29 (m, 4H),6.24-6.16 (m, 2H), 4.59 (q, J=5.1 Hz, 1H), 4.09 (td, J=7.7, 2.8 Hz, 1H),3.95 (dd, J=21.8, 13.1 Hz, 1H), 3.60 (hept, J=6.1 Hz, 1H), 3.44-3.19 (m,4H), 2.35 (s, 3H), 2.16-2.03 (m, 1H), 1.99-1.79 (m, 3H), 1.78-1.60 (m,6H), 1.30-1.17 (m, 2H), 1.04 (d, J=6.1 Hz, 5H), 0.88 (td, J=7.4, 1.0 Hz,3H).

Example 5-22-[1-(4-chlorophenyl)butyl]-7-(3,3-difluoropiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine

The synthesis was done analogously to the synthesis described in EXAMPLE2-8 to obtain the titled compound as a clear oil (84%). LC-MS (ESI+) m/z419.2 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.41-7.30 (m, 4H), 6.31(s, 1H), 6.26 (s, 1H), 4.29 (t, J=11.8 Hz, 2H), 4.13 (t, J=7.8 Hz, 1H),3.67 (t, J=5.3 Hz, 2H), 3.31 (d, J=8.7 Hz, 1H), 2.39 (s, 3H), 2.21-2.05(m, 3H), 2.00-1.86 (m, 3H), 1.23 (dddd, J=14.5, 10.9, 7.3, 5.3 Hz, 2H),0.88 (t, J=7.3 Hz, 3H).

Preparation of Compounds Derived from Intermediate a6 Example 6-12-(1-{5-methyl-2-[3-(trifluoromethyl)benzyl]pyrazolo[1,5-a]pyrimidin-7-yl}piperidin-2-yl)ethanol

A mixture of7-chloro-5-methyl-2-[3-(trifluoromethyl)benzyl]pyrazolo[1,5-a]pyrimidine(80 mg, 0.246 mmol, INTERMEDIATE a6), 2-(piperidin-2-yl)ethanol) (63.5mg, 0.491 mmol), and N-ethyl-N-isopropylpropan-2-amine (127 mg, 0.982mmol) in ethanol (3 mL) was stirred at room temperature for 12 h andthen at 50° C. for 6 h.

For work-up, the reaction mixture was extracted with H₂O/CH₂Cl₂, and thecombined organic layers were washed with brine, dried over MgSO₄,filtered, and concentrated. After chromatographic purification using aTeledyne Isco CombiFlash® system (normal phase: 4 g column, eluent: 3-5%CH₃OH/CH₂Cl₂), the titled compound was obtained as a clear oil (38 mg,37.0%). LC-MS (ESI+) m/z 419.2 [M+H]⁺; ¹H NMR (600 MHz, DMSO-d₆) δ ppm7.72 (t, J=1.7 Hz, 1H), 7.64-7.50 (m, 3H), 6.26 (s, 1H), 6.15 (s, 1H),4.97 (d, J=7.7 Hz, 1H), 4.61 (t, J=5.2 Hz, 1H), 4.17 (s, 2H), 3.96 (d,J=12.7 Hz, 1H), 3.41-3.19 (m, 3H), 2.37 (s, 3H), 1.91-1.56 (m, 8H), 1.04(d, J=6.1 Hz, 2H).

Preparation of Compounds Derived from Intermediate a7 Example 7-12-{1-[5-methyl-2-(tricyclo[3.3.1.1³′]dec-1-ylmethyl)pyrazolo[1,5-a]pyrimidin-7-yl]piperidin-2-yl}ethanol

A mixture of INTERMEDIATE a7 (80 mg, 0.253 mmol),2-(piperidin-2-yl)ethanol (65.5 mg, 0.507 mmol), andN-ethyl-N-isopropylpropan-2-amine (131 mg, 1.013 mmol) in ethanol (3 mL)was stirred at room temperature for 36 h and then at 50° C. for 6 h.

For work-up, the reaction mixture was extracted with H₂O/CH₂Cl₂, and thecombined organic layers were washed with brine, dried over MgSO₄,filtered, and concentrated. The resultant residue waschromatographically purified using a Teledyne Isco CombiFlash® system(normal phase: 4 g column, eluent: 3-5% CH₃OH/CH₂Cl₂). The materialobtained from the chromatography was triturated with ethylacetate/diisopropyl ether, and the resultant solid was collected byfiltration and dried in a vacuum oven overnight to give the titledcompound as a white solid (15 mg, 15.0%). LC-MS (ESI+) m/z 409.4 [M+H]⁺;¹H NMR (600 MHz, DMSO-d₆) δ ppm 6.22 (s, 1H), 6.07 (s, 1H), 5.05 (s,1H), 4.67 (dd, J=6.0, 4.7 Hz, 1H), 3.90 (d, J=13.0 Hz, 1H), 3.46-3.35(m, 2H), 3.35-3.21 (m, 3H), 2.44 (s, 2H), 2.37 (s, 3H), 1.93-1.83 (m,4H), 1.83-1.58 (m, 11H), 1.57-1.49 (m, 9H).

Preparation of Compounds Derived from Intermediate a8 Example 8-1(2S)-1-(5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)azetidine-2-carboxamide

A drop of N,N-dimethylformamide and oxalyl dichloride (2.5 mL) wereadded to a solution of(2S)-1-(5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)azetidine-2-carboxylicacid (100 mg, 0.247 mmol, EXAMPLE 8-10) in dichloromethane (1 mL). Thevessel was flushed with argon, and then the mixture was stirred at roomtemperature for 5 hours. The mixture was then concentrated, and theresidue was diluted with dichloromethane (3 mL). Ammonium hydroxide (2.5mL, aqueous 15 M solution) was added, and the reaction solution wasstirred at room temperature overnight. The crude residue was purified byflash chromatography, C18 column (CH₃OH/water: gradient from 5:95 to50:50) provided the titled compound (53.4 mg, 53%). MS (ESI+) m/z 404.1[M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 1.72 (d, 3H), 2.40 (m, 4H), 2.88(m, 1H), 4.25 (m, 1H), 4.32 (m, 1H), 4.42 (m, 1H), 5.50 (m, 1H), 5.71(s, 1H), 5.98 (d, 1H), 7.48 (d, 2H), 7.60 (d, 2H).

Example 8-22-[1-(5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)piperidin-2-yl]ethanol

7-Chloro-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine(100 mg, 0.294 mmol, INTERMEDIATE a8) and 2-(piperidin-2-yl)ethanol (76mg, 0.589 mmol) were added to a solution of triethylamine (0.123 mL,0.883 mmol) in acetonitrile (2 mL). The reaction mixture was stirredovernight at 60° C. under nitrogen and then cooled down to roomtemperature. Water and ethyl acetate were added, the organic layer wasseparated and the aqueous layer was extracted with ethyl acetate. Thecombined organic layers were washed with water and dried over sodiumsulfate. After filtration and concentration under reduced pressure, theresidue was purified by preparative-HPLC, Column: Waters XBridge® C18,19×150 mm, 5 μm; Mobile Phase A: water/10 mM NH₄HCO₃, Mobile Phase B:acetonitrile; Flow rate: 20 mL/minute; Gradient: 38% B to 52% B in 8minutes; 254 nm, to provide the titled compound (31.3 mg, 24.6%) as awhite solid. MS (ESI+) m/z 433.1 [M+H]⁺; NMR (400 MHz, CD₃OD) δ ppm 1.75(m, 6H), 1.84 (m, 4H), 2.17 (m, 1H), 2.41 (s, 3H), 3.42 (m, 1H), 3.63(m, 2H), 3.92 (d, 1H), 4.39 (q, 1H), 5.15 (m, 1H), 6.12 (d, 1H), 6.25(s, 1H), 7.47 (d, 2H), 7.54 (d, 2H).

Example 8-35-methyl-7-(2-oxa-6-azaspiro[3.4]oct-6-yl)-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine

7-Chloro-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine(100 mg, 0.294 mmol, INTERMEDIATE a8) was added to a suspension ofpotassium carbonate (122 mg, 0.883 mmol) and 2-oxa-6-azaspiro[3.4]octane(40.0 mg, 0.353 mmol) in N,N-dimethylformamide (4 mL). The mixture wasstirred at 60° C. overnight. The reaction mixture was partitionedbetween water and ethyl acetate, the organic layer was separated, andthe aqueous layer was extracted with ethyl acetate. The combined organiclayers were washed with water, dried over sodium sulfate, andconcentrated. Purification of the residue by preparative-HPLC (column:Waters XBridge® C18, 19×150 mm, 5 m; mobile phase A: water/10 mMNH₄HCO₃, mobile phase B: acetonitrile; flow rate: 25 mL/minute;gradient: 25% B to 60% B in 10 minutes; 254 nm) provided the titledcompound (8.1 mg, 6.6%). MS(ESI+) m/z 417.1 [M+H]⁺; ¹H NMR (400 MHz,CD₃OD) δ ppm 1.73 (d, 3H), 2.33 (t, 2H), 2.37 (s, 3H), 3.97 (t, 2H),4.26 (s, 2H), 4.39 (q, 1H), 4.67 (d, 2H), 4.72 (d, 2H), 5.79 (s, 1H),6.02 (s, 1H), 7.52 (d, 2H), 7.60 (d, 2H).

Example 8-45-methyl-7-(7-oxa-2-azaspiro[3.5]non-2-yl)-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine

7-Chloro-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine(60 mg, 0.177 mmol, INTERMEDIATE a8) was added to a solution of7-oxa-2-azaspiro[3.5]nonane (57.8 mg, 0.353 mmol) and triethylamine(0.098 mL, 0.706 mmol) in acetonitrile (3 mL). The mixture was stirredat 60° C. overnight under nitrogen. The residue was purified bypreparative-HPLC (column: Waters SunFire® C18 19×150 mm, 5 μm; mobilephase A: water/0.05% trifluoroacetic acid, mobile phase B: acetonitrile;flow rate: 20 mL/minute; gradient: 15% B to 50% B in 9 minutes; 254 nm)the titled compound as a trifluoroacetic acid salt (70 mg, 72.8%).MS(ESI+) m/z 431.2 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 1.75 (d, 3H),1.94 (t, 4H), 2.51 (s, 3H), 3.32 (s, 2H), 3.70 (t, 4H), 4.25 (s, 2H),4.44 (q, 1H), 5.95 (s, 1H), 6.18 (s, 1H), 7.54 (d, 2H), 7.63 (d, 2H).

Example 8-5(3R)-1-(5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)piperidin-3-ol

7-Chloro-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine(80 mg, 0.235 mmol, INTERMEDIATE a8) was added to a solution oftriethylamine (23.8 mg, 0.235 mmol) and (R)-piperidin-3-ol (47.6 mg,0.471 mmol) in acetonitrile (2 mL). The resulting solution was stirredovernight at 60° C. under nitrogen. The reaction mixture was partitionedbetween water and ethyl acetate, the organic layer was separated, andthe aqueous layer was extracted with ethyl acetate. The combined organiclayers were washed with water, dried over sodium sulfate andconcentrated. Purification of the residue by preparative-HPLC: column:Waters XBridge® C18, 19×150 mm, 5 μm; mobile phase A: water/10 mMNH₄HCO₃, mobile phase B: acetonitrile; flow rate: 20 mL/minute;gradient: 45% B to 58% B in 8 minutes; 254 nm) provided the titledcompound (20.8 mg, 21.8%). MS(ESI+) m/z 405.2 [M+H]⁺; ¹H NMR (400 MHz,CD₃OD) δ ppm 1.65 (m, 1H), 1.75 (m, 4H), 2.04 (m, 2H), 2.46 (s, 3H),3.36 (m, 2H), 3.90 (m, 1H), 4.00 (m, 1H), 4.21 (d, 1H), 4.44 (q, 1H),6.18 (s, 1H), 6.21 (d, 1H), 7.55 (d, 2H), 7.61 (d, 2H).

Example 8-6N-(3-fluorocyclobutyl)-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-amine

7-Chloro-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine(80 mg, 0.235 mmol, INTERMEDIATE a8) was added to a suspension ofpotassium carbonate (98 mg, 0.706 mmol) and 3-fluorocyclobutanamine(42.0 mg, 0.471 mmol) in N,N-dimethylformamide (3 mL). The vessel wasflushed with argon, and then the mixture was stirred and heated in amicrowave (100° C., 300 W, 1 hour). The reaction mixture was partitionedbetween water and ethyl acetate, the organic layer was separated, andthe aqueous layer was extracted with ethyl acetate. The combined organiclayers were washed with water, dried over sodium sulfate, andconcentrated. Purification of the residue by preparative-HPLC (column:Waters XBridge® C18, 19×150 mm, 5 μm; mobile phase A: Water/10 mMNH₄HCO₃, mobile phase B: acetonitrile; flow rate: 20 mL/minute;gradient: 45% B to 58% B in 8 minutes; 254 nm) provided the titledcompound (14.6 mg, 15.8%). MS(ESI+) m/z 393.1 [M+H]⁺; ¹H NMR (400 MHz,CD₃OD) δ ppm 1.76 (d, 3H), 2.38 (m, 1H), 2.45 (s, 3H), 2.60 (m, 1H),2.75 (m, 1H), 3.02 (m, 1H), 3.81 (m, 0.6H), 4.45 (m, 1.4H), 4.90 (dm,0.6H), 5.28 (dm, 0.4H), 5.91 (m, 1H), 6.16 (m, 1H), 7.52 (m, 2H), 7.61(m, 2H).

Example 8-7N-[(3S)-1-(5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)pyrrolidin-3-yl]acetamide

7-Chloro-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine(100 mg, 0.294 mmol, INTERMEDIATE a8) was added to a solution oftriethylamine (89 mg, 0.883 mmol) and (S)—N-(pyrrolidin-3-yl)acetamide(75 mg, 0.589 mmol) in acetonitrile (2 mL). The resulting solution wasstirred overnight at 60° C. under nitrogen. The reaction mixture waspartitioned between water and ethyl acetate, the organic layer wasseparated, and the aqueous layer was extracted with ethyl acetate. Thecombined organic layers were washed with water, dried over sodiumsulfate, and concentrated. Purification of the residue bypreparative-HPLC: column: Waters XBridge® C18, 19×150 mm, 5 μm; mobilephase A: water/10 mM NH₄HCO₃, mobile phase B: acetonitrile; flow rate:20 mL/minute; gradient: 39% B to 53% B in 8 minutes; 254 nm) providedthe titled compound (58.6 mg, 46.1%). MS(ESI+) m/z 432.1 [M+H]⁺; ¹H NMR(400 MHz, CD₃OD) δ ppm 1.68 (d, 3H), 1.90 (s, 3H), 1.97 (m, 1H), 2.21(m, 1H), 2.33 (s, 3H), 3.96 (m, 3H), 4.19 (m, 1H), 4.31 (q, 1H), 4.43(m, 1H), 5.74 (s, 1H), 5.98 (s, 1H), 7.47 (d, 2H), 7.55 (d, 2H).

Example 8-85-methyl-N-(1-methylcyclopropyl)-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-amine

7-Chloro-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine(100 mg, 0.294 mmol, INTERMEDIATE a8) was added to a suspension of1-methylcyclopropanamine hydrochloride (95 mg, 0.883 mmol) and potassiumcarbonate (122 mg, 0.883 mmol) in N,N-dimethylformamide (3 mL). Thevessel was flushed with argon, and then the mixture was stirred andheated in a microwave (100° C., 300 W, 1 hour). The reaction mixture waspartitioned between water and ethyl acetate, the organic layer wasseparated, and the aqueous layer was extracted with ethyl acetate. Thecombined organic layers were washed with water, dried over sodiumsulfate, and concentrated. Purification of the residue bypreparative-HPLC (column: Waters XBridge® C18, 19×150 mm, 5 μm; mobilephase A: water/10 mM NH₄HCO₃, mobile phase B: acetonitrile; flow rate:20 mL/minute; gradient: 45% B to 58% B in 8 minutes; 254 nm) providedthe titled compound (17.7 mg, 16.1%). MS(ESI+) m/z 375.1 [M+H]⁺; ¹H NMR(400 MHz, CD₃OD) δ ppm 1.01 (m, 2H), 1.09 (m, 2H), 1.56 (s, 3H), 1.78(d, 3H), 2.64 (s, 3H), 4.51 (q, 1H), 6.30 (s, 1H), 6.58 (s, 1H), 7.55(d, 2H), 7.63 (d, 2H).

Example 8-9[1-(5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)piperidin-2-yl]methanol

7-Chloro-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine(80 mg, 0.235 mmol, INTERMEDIATE a8) was added to a suspension ofpiperidin-2-ylmethanol (81 mg, 0.706 mmol) and potassium carbonate (98mg, 0.706 mmol) in 1,4-dioxane (2 mL). The resulting solution wasstirred at 120° C. for 48 hours. The reaction mixture was partitionedbetween water and ethyl acetate, the organic layer was separated, andthe aqueous layer was extracted with ethyl acetate. The combined organiclayers were washed with water, dried over sodium sulfate, andconcentrated. Purification of the residue by preparative-HPLC: column:Waters XBridge® C18, 19×150 mm, 5 μm; mobile phase A: water/10 mMNH₄HCO₃, mobile phase B: acetonitrile; flow rate: 20 mL/minute;gradient: 45% B to 58% B in 8 minutes; 254 nm) provided the titledcompound (20.4 mg, 20.7%). MS(ESI+) m/z 419.1 [M+H]⁺; ¹H NMR (400 MHz,CD₃OD) δ ppm 1.77 (m, 8H), 1.91 (m, 1H), 2.45 (s, 3H), 3.46 (m, 1H),3.67 (q, 1H), 3.84 (m, 1H), 4.03 (m, 1H), 4.42 (q, 1H), 5.14 (m, 1H),6.16 (d, 1H), 6.24 (s, 1H), 7.54 (d, 2H), 7.61 (d, 2H).

Example 8-10(2S)-1-(5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)azetidine-2-carboxylicacid

7-Chloro-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine(200 mg, 0.589 mmol, INTERMEDIATE a8) was added to a suspension of(S)-azetidine-2-carboxylic acid (119 mg, 1.177 mmol) and potassiumcarbonate (244 mg, 1.766 mmol) in 1,4-dioxane (5 mL). The mixture wasstirred at 50° C. for 48 hours and then concentrated under vacuum.Purification of the residue by flash chromatography on silica gel elutedwith methanol/dichloromethane (gradient from 0:1 to 1:3) provided thetitled compound (26.1 mg, 11%). MS(ESI+) m/z 405.1 [M+H]⁺; ¹H NMR (400MHz, CD₃OD) δ ppm 1.70 (d, 3H), 2.38 (m, 4H), 2.89 (m, 1H), 3.37 (s,3H), 4.33 (q, 1H), 5.69 (s, 1H), 5.98 (s, 1H), 7.54 (d, 2H), 7.60 (d,2H).

Example 8-117-(4-fluoropiperidin-1-yl)-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine

7-Chloro-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine(60 mg, 0.177 mmol, INTERMEDIATE a8) was added to a solution of4-fluoropiperidine hydrochloride (49.3 mg, 0.353 mmol) and triethylamine(0.098 mL, 0.706 mmol) in acetonitrile (3 mL). The mixture was stirredat 60° C. overnight under nitrogen and then concentrated. The cruderesidue was purified by preparative-HPLC (column: Waters SunFire® C1819×150 mm, 5 μm; mobile phase A: water/0.05% trifluoroacetic acid,mobile phase B: acetonitrile; flow rate: 20 mL/minute; gradient: 15% Bto 50% B in 11 minutes; 254 nm) to provide the titled compound as atrifluoroacetic acid salt (55 mg, 59.8%). MS(ESI+) m/z 407.1 [M+H]⁺; ¹HNMR (400 MHz, CD₃OD) δ ppm 1.77 (d, 3H), 2.12 (m, 4H), 2.56 (s, 3H),4.14 (m, 2H), 4.48 (q, 1H), 4.50 (m, 2H), 5.06 (m, 1H), 6.29 (s, 1H),6.51 (s, 1H), 7.55 (d, 2H), 7.63 (d, 2H).

Example 8-127-(3-fluoropiperidin-1-yl)-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine

7-Chloro-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine(100 mg, 0.294 mmol, INTERMEDIATE a8) was added to a suspension of3-fluoropiperidine (91 mg, 0.883 mmol) and potassium carbonate (81 mg,0.589 mmol) in 1,4-dioxane (3 mL). The mixture was stirred at 50° C. for48 hours and then concentrated under vacuum. Purification of the residueby flash chromatography on silica gel eluted with ethylacetate/petroleum ether (gradient ethyl acetate:petroleum ether from 0:1to 1:1) provided the titled compound (20.9 mg, 17.5%). MS(ESI+) m/z407.1 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 1.72 (m, 1H), 1.76 (d, 3H),2.05 (m, 3H), 2.46 (s, 3H), 3.58 (m, 1H), 3.88 (m, 2H), 4.19 (m, 1H),4.43 (q, 1H), 4.77 (m, 0.7H), 4.88 (m, 0.3H), 6.17 (s, 1H), 6.22 (s,1H), 7.53 (d, 2H), 7.61 (d, 2H).

Example 8-133-(2-hydroxyethyl)-4-(5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)piperazin-2-one

7-Chloro-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine(100 mg, 0.294 mmol, INTERMEDIATE a8) was added to a suspension of3-(2-hydroxyethyl)piperazin-2-one (42.4 mg, 0.294 mmol) and potassiumcarbonate (61.0 mg, 0.442 mmol) in N,N-dimethylformamide (4 mL). Themixture was stirred at 65° C. overnight and then concentrated undervacuum. The residue was purified by preparative-HPLC (column: WatersXBridge® C18, 19×150 mm, 5 μm; mobile phase A: water/0.05%trifluoroacetic acid, mobile phase B: acetonitrile; flow rate: 25mL/minute; gradient: 25% B to 60% B in 10 minutes; 254 nm) to providethe titled compound as a trifluoroacetic acid salt (44.0 mg, 26.6%).MS(ESI+) m/z 448.1 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 1.76 (d, 3H),2.35 (m, 2H), 2.54 (s, 3H), 3.42 (m, 1H), 3.63 (m, 2H), 3.84 (m, 2H),4.49 (q, 1H), 5.31 (brs, 1H), 5.60 (brs, 1H), 6.30 (s, 1H), 6.72 (s,1H), 7.53 (d, 2H), 7.61 (d, 2H).

Example 8-14N-[(3,3-difluorocyclobutyl)methyl]-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-amine

7-Chloro-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine(100 mg, 0.294 mmol, INTERMEDIATE a8) was added to a suspension of(3,3-difluorocyclobutyl)methanamine (39.2 mg, 0.324 mmol) and sodiumcarbonate (62.4 mg, 0.589 mmol) in N,N-dimethylformamide (3 mL). Thevessel was flushed with argon, and then the mixture was stirred andheated in the microwave (100° C., 300 W, 1 hour). The final mixture wasconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluted with ethyl acetate/petroleum ether(gradient ethyl acetate:petroleum ether from 0:1 to 1:1) to provide thetitled compound (57.8 mg, 46.3%). MS(ESI+) m/z 425.2 [M+H]⁺; ¹H NMR (400MHz, CD₃OD) δ ppm 1.79 (d, 3H), 2.47 (m, 2H), 2.60 (s, 3H), 2.75 (m,3H), 3.76 (d, 2H), 4.54 (q, 1H), 6.32 (s, 1H), 6.53 (s, 1H), 7.55 (d,2H), 7.63 (d, 2H).

Example 8-157-(3,3-difluoropyrrolidin-1-yl)-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine

7-Chloro-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine(60 mg, 0.177 mmol, INTERMEDIATE a8) was added to a solution of3,3-difluoropyrrolidine hydrochloride (50.7 mg, 0.353 mmol) andtriethylamine (0.098 mL, 0.706 mmol) in acetonitrile (3 mL). The mixturewas stirred at 60° C. overnight under nitrogen. The residue was purifiedby preparative-HPLC (column: Waters SunFire® C18 19×150 mm, 5 μm; mobilephase A: water/0.05% trifluoroacetic acid, mobile phase B: acetonitrile;flow rate: 20 mL/minute; gradient: 10% B to 55% B in 9 minutes; 254 nm)to provide the titled compound as a trifluoroacetic acid salt (46.3 mg,50.0%). MS(ESI+) m/z 411.2 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 1.77(d, 3H), 2.56 (s, 3H), 2.68 (m, 2H), 4.39 (m, 2H), 4.48 (q, 1H), 4.73(m, 2H), 6.24 (s, 1H), 6.27 (s, 1H), 7.55 (d, 2H), 7.64 (d, 2H).

Example 8-16N-[(3R)-1-(5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)pyrrolidin-3-yl]acetamide

7-Chloro-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine(50 mg, 0.147 mmol, INTERMEDIATE a8) was added to a solution oftriethylamine (44.7 mg, 0.442 mmol) and (R)—N-(pyrrolidin-3-yl)acetamide(18.9 mg, 0.147 mmol) in acetonitrile (2 mL). The resulting solution wasstirred overnight at 60° C. under nitrogen. The reaction mixture waspartitioned between water and ethyl acetate, the organic layer wasseparated, and the aqueous layer was extracted with ethyl acetate. Thecombined organic layers were washed with water, dried over sodiumsulfate, and concentrated. Purification of the residue bypreparative-HPLC (column: Waters XBridge® C18, 19×150 mm, 5 m; mobilephase A: water/10 mM NH₄HCO₃, mobile phase B: acetonitrile; flow rate:20 mL/minute; gradient: 38% B to 52% B in 8 minutes; 254 nm) providedthe titled compound (32.9 mg, 51.8%). MS(ESI+) m/z 432.1 [M+H]⁺; ¹H NMR(400 MHz, CD₃OD) δ ppm 1.68 (d, 3H), 1.90 (s, 3H), 2.01 (m, 1H), 2.21(m, 1H), 2.33 (s, 3H), 3.94 (m, 3H), 4.23 (m, 1H), 4.34 (q, 1H), 4.45(m, 1H), 5.76 (s, 1H), 5.99 (s, 1H), 7.49 (d, 2H), 7.56 (d, 2H).

Example 8-177-(3,3-difluoropiperidin-1-yl)-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine

7-Chloro-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine(60 mg, 0.177 mmol, INTERMEDIATE a8) was added to a solution of3,3-difluoropiperidine hydrochloride (55.7 mg, 0.353 mmol) andtriethylamine (0.098 mL, 0.706 mmol) in acetonitrile (3 mL). The mixturewas stirred at 60° C. overnight under nitrogen. The residue was purifiedby preparative-HPLC (column: Waters SunFire® C18 19×150 mm, 5 m; mobilephase A: water/0.05% trifluoroacetic acid, mobile phase B: acetonitrile;flow rate: 20 mL/minute; gradient: 15% B to 50% B in 9 minutes; 254 nm)to provide the titled compound (13.6 mg, 18.14%). MS(ESI+) m/z 425.1[M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 1.76 (d, 3H), 2.01 (m, 2H), 2.19(m, 2H), 2.48 (s, 3H), 3.78 (m, 2H), 4.27 (m, 2H), 4.46 (q, 1H), 6.20(s, 1H), 6.26 (s, 1H), 7.54 (d, 2H), 7.61 (d, 2H).

Example 8-181-(5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)piperidin-2-one

(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (6.81 mg,0.012 mmol) was added to a suspension of7-chloro-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine(80 mg, 0.235 mmol, INTERMEDIATE a8), cesium carbonate (230 mg, 0.706mmol), palladium(II) acetate (52.9 mg, 0.235 mmol) and piperidin-2-one(23.34 mg, 0.235 mmol) in N,N-dimethylformamide (3 mL). The resultingsolution was stirred at 130° C. for 48 hours. The reaction mixture waspartitioned between water and ethyl acetate, the organic layer wasseparated, and the aqueous layer was extracted with ethyl acetate. Thecombined organic layers were washed with water, dried over sodiumsulfate, and concentrated. Purification of the residue bypreparative-HPLC (column: Waters SunFire® C18, 19×150 mm, 5 μm; mobilephase A: water/0.05% trifluoroacetic acid, mobile phase B: acetonitrile;flow rate: 30 mL/minute; gradient: 28% B to 60% B in 11 minutes; 254 nm)provided the titled compound as a trifluoroacetic acid salt (9.7 mg,7.98%). MS(ESI+) m/z 403.1 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 1.78(d, 3H), 2.05 (m, 4H), 2.60 (s, 3H), 2.63 (m, 2H), 3.80 (m, 2H), 4.47(q, 1H), 6.48 (s, 1H), 6.92 (s, 1H), 7.53 (d, 2H), 7.61 (d, 2H).

Example 8-19N-tert-butyl-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-amine

7-Chloro-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine(80 mg, 0.235 mmol, INTERMEDIATE a8) was added to a suspension ofpotassium carbonate (98 mg, 0.706 mmol) and 2-methylpropan-2-amine (51.7mg, 0.706 mmol) in N,N-dimethylformamide (2 mL). The vessel was flushedwith argon, and then the mixture was stirred and heated in a microwave(100° C., 300 W, 1 hour). The reaction mixture was partitioned betweenwater and ethyl acetate, the organic layer was separated, and theaqueous layer was extracted with ethyl acetate. The combined organiclayers were washed with water, dried over sodium sulfate, andconcentrated. Purification of the residue by preparative-HPLC (column:Waters XBridge® C18, 19×150 mm, 5 m; mobile phase A: water/10 mMNH₄HCO₃, mobile phase B: acetonitrile; flow rate: 20 mL/minute;gradient: 45% B to 58% B in 8 minutes; 254 nm) provided the titledcompound (33.9 mg, 29.4%). MS(ESI+) m/z 377.1 [M+H]⁺; ¹H NMR (400 MHz,CD₃OD) δ ppm 1.66 (s, 9H), 1.78 (d, 3H), 2.64 (s, 3H), 4.54 (q, 1H),6.34 (m, 1H), 6.64 (s, 1H), 7.56 (d, 2H), 7.64 (d, 2H).

Example 8-20N-(3,3-difluorocyclobutyl)-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-amine

7-Chloro-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine(100 mg, 0.294 mmol, INTERMEDIATE a8) was added to a suspension ofpotassium carbonate (122 mg, 0.883 mmol) and 3,3-difluorocyclobutanamine(63 mg, 0.589 mmol) in N,N-dimethylformamide (3 mL). The vessel wasflushed with argon, and then the mixture was stirred and heated in amicrowave (100° C., 300 W, 1 hour). The reaction mixture was partitionedbetween water and ethyl acetate, the organic layer was separated, andthe aqueous layer was extracted with ethyl acetate. The combined organiclayers were washed with water, dried over sodium sulfate, andconcentrated. Purification of the residue by preparative-HPLC (column:Waters HSS C18, 2.1×50 mm, 1.8 μm; mobile phase A: water/0.05%trifluoroacetic acid, mobile phase B: acetonitrile/0.05% trifluoroaceticacid B: acetonitrile; flow rate: 0.7 mL/minute; gradient: 5% B to 55% Bin 8.0 minutes; 254 nm) provided the titled compound as atrifluoroacetic acid salt (64 mg, 41.5%). MS(ESI+) m/z 411.1 [M+H]⁺; ¹HNMR (400 MHz, CD₃OD) δ ppm 1.78 (d, 3H), 2.60 (s, 3H), 2.99 (m, 2H),3.18 (m, 2H), 4.42 (m, 1H), 4.53 (q, 1H), 6.34 (s, 1H), 6.41 (s, 1H),7.56 (d, 2H), 7.63 (d, 2H).

Example 8-215-methyl-7-(2-oxa-7-azaspiro[3.5]non-7-yl)-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine

7-Chloro-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine(100 mg, 0.294 mmol, INTERMEDIATE a8) was added to a suspension of2-oxa-7-azaspiro[3.5]nonane (74.9 mg, 0.589 mmol) and potassiumcarbonate (122 mg, 0.883 mmol) in 1,4-dioxane (3 mL). The mixture wasstirred at 50° C. for 48 hours and then concentrated under vacuum.Purification of the residue by flash chromatography on silica gel elutedwith ethyl acetate/petroleum ether (gradient ethyl acetate:petroleumether from 0:1 to 1:1) provided the titled compound (31.3 mg, 24.7%).MS(ESI+) m/z 431.2 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 1.72 (d, 3H),1.89 (t, 4H), 2.38 (s, 3H), 3.69 (t, 4H), 4.28 (m, 4H), 4.36 (q, 1H),5.63 (s, 1H), 6.01 (s, 1H), 7.52 (d, 2H), 7.60 (d, 2H).

Example 8-221-(5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)pyrrolidine-3-carboxamide

7-Chloro-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine(100 mg, 0.294 mmol, INTERMEDIATE a8) was added to a suspension ofpyrrolidine-3-carboxamide (40.3 mg, 0.353 mmol) and sodium carbonate(62.4 mg, 0.589 mmol) in N,N-dimethylformamide (5 mL). The vessel wasflushed with argon, and then the mixture was stirred and heated in amicrowave (100° C., 300 W, 1 hour). The final mixture was concentratedunder vacuum. Purification of the residue by flash chromatography onsilica gel eluted with ethyl acetate/petroleum ether (gradient ethylacetate:petroleum ether from 0:1 to 1:1) provided the titled compound(27.7 mg, 22.54%). MS(ESI+) m/z 418.2 [M+H]⁺; ¹H NMR (400 MHz, CDCl3)1.68 (d, 3H), 2.37 (m, 2H), 2.50 (s, 3H), 3.27 (m, 1H), 4.06 (m, 1H),4.29 (q, 1H), 4.70 (m, 1H), 5.70 (m, 2H), 6.33 (s, 1H), 6.55 (s, 1H),7.37 (d, 2H), 7.55 (d, 2H).

Preparation of Compounds Derived from Intermediate a9 Example 9-1(1-{2-[1-(5-chloropyridin-2-yl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}piperidin-3-yl)methanol

7-Chloro-2-[1-(5-chloropyridin-2-yl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidine(100 mg, 0.326 mmol, INTERMEDIATE a9) was added to a suspension ofpotassium carbonate (45.0 mg, 0.326 mmol) and piperidin-3-ylmethanol(41.2 mg, 0.358 mmol) in N,N-dimethylformamide (6 mL). The mixture wasstirred at 50° C. overnight. The reaction mixture was partitionedbetween water and ethyl acetate, the organic layer was separated, andthe aqueous layer was extracted with ethyl acetate. The combined organiclayers were washed with water, dried over sodium sulfate, andconcentrated. Purification of the residue by preparative-HPLC (column:Waters XBridge® C18, 19×150 mm, 5 μm; mobile phase A: Water/10 mMNH₄HCO₃, mobile phase B: acetonitrile; flow rate: 20 mL/minute;gradient: 30% B to 70% B in 10 minutes; 254 nm) provided the titledcompound (44.1 mg, 35.1%). MS (ESI+) m/z 386.1 [M+H]⁺; ¹H NMR (400 MHz,CD₃OD) δ ppm 1.41 (m, 1H), 1.72 (d, 3H), 1.85 (m, 4H), 2.41 (s, 3H),3.15 (m, 2H), 3.52 (m, 2H), 4.17 (m, 2H), 4.45 (q, 1H), 6.17 (d, 2H),7.39 (d, 1H), 7.76 (d, 1H), 8.41 (s, 1H).

Example 9-22-[1-(5-chloropyridin-2-yl)ethyl]-N-(3,3-difluorocyclobutyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-amine

7-Chloro-2-[1-(5-chloropyridin-2-yl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidine(80 mg, 0.260 mmol, INTERMEDIATE a9) was added to a suspension of cesiumcarbonate (85 mg, 0.26 mmol), 3,3-difluorocyclobutanamine hydrochloride(37.4 mg, 0.260 mmol) and potassium iodide (43.2 mg, 0.260 mmol) in1,4-dioxane (5 mL). The mixture was stirred at 100° C. for 10 hours thenconcentrated under vacuum. The residue was purified by preparative-HPLC(column: Waters XBridge® C18, 19×150 mm, 5 μm; mobile phase A:Water/0.5% NH₄HCO₃, mobile phase B: acetonitrile; flow rate: 20mL/minute; gradient: 30% B to 70% B in 10 minutes; 254 nm) to providethe titled compound (26.7 mg, 27.1%). MS(ESI+) m/z 378.1 [M+H]⁺; ¹H NMR(400 MHz, CD₃OD) δ ppm 1.74 (d, 3H), 2.42 (s, 3H), 2.79 (m, 2H), 3.13(m, 2H), 4.13 (m, 1H), 4.48 (q, 1H), 5.95 (s, 1H), 6.16 (s, 1H), 7.37(d, 1H), 7.75 (d, 1H), 8.45 (s, 1H).

Example 9-3(3S)-1-{2-[1-(5-chloropyridin-2-yl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}piperidin-3-ol

7-Chloro-2-[1-(5-chloropyridin-2-yl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidine(80 mg, 0.260 mmol, INTERMEDIATE a9) was added to a solution of(S)-piperidin-3-ol (52.7 mg, 0.521 mmol) and triethylamine (79 mg, 0.781mmol) in acetonitrile (10 mL). The mixture was stirred at 80° C. for 4hours and then concentrated under vacuum. The residue was purified bypreparative-HPLC (column: Waters XBridge® C18, 19×150 mm, 5 μm; mobilephase A: water/0.05% NH₄HCO₃, mobile phase B: acetonitrile; flow rate:20 mL/minute; gradient: 30% B to 70% B in 10 minutes; 254 nm) providedthe titled compound (55.4 mg, 57.2%). MS(ESI+) m/z 372.1 [M+H]⁺; ¹H NMR(400 MHz, CD₃OD) δ ppm 1.69 (m, 2H), 1.78 (d, 3H), 2.03 (m, 2H), 2.47(s, 3H), 3.36 (m, 2H), 3.90 (m, 2H), 4.19 (m, 1H), 4.51 (q, 1H), 6.21(m, 2H), 7.42 (d, 1H), 7.80 (d, 1H), 8.49 (s, 1H).

Example 9-42-[1-(5-chloropyridin-2-yl)ethyl]-7-(3,3-difluoropiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine

7-Chloro-2-[1-(5-chloropyridin-2-yl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidine(60 mg, 0.195 mmol, INTERMEDIATE a9) was added to a suspension ofpotassium carbonate (81 mg, 0.586 mmol) and 3,3-difluoropiperidine (71.0mg, 0.586 mmol) in 1,4-dioxane (10 mL). The mixture was stirred at 100°C. for 10 hours and then concentrated under vacuum. The crude residuewas purified by preparative-HPLC (column: Waters XBridge® C18, 19×150mm, 5 μm; mobile phase A: water/0.5% NH₄HCO₃, mobile phase B:acetonitrile; flow rate: 20 mL/minute; gradient: 30% B to 70% B in 10minutes; 254 nm) to provide the titled compound (32 mg, 41.8%). MS(ESI+)m/z 392.0 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 1.78 (d, 3H), 1.97 (m,2H), 2.17 (m, 2H), 2.48 (s, 3H), 3.76 (m, 2H), 4.22 (m, 2H), 4.51 (q,1H), 6.24 (s, 1H), 6.26 (s, 1H), 7.41 (d, 1H), 7.80 (d, 1H), 8.49 (s,1H).

Example 9-52-[1-(5-chloropyridin-2-yl)ethyl]-7-(3,3-difluoropyrrolidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine

7-Chloro-2-[1-(5-chloropyridin-2-yl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidine(60 mg, 0.195 mmol, INTERMEDIATE a9) was added to a suspension of3,3-difluoropyrrolidine hydrochloride (84 mg, 0.586 mmol) and potassiumcarbonate (81 mg, 0.586 mmol) in 1,4-dioxane (10 mL). The mixture wasstirred at 100° C. for 10 hours and then concentrated under vacuum. Thecrude residue was purified by preparative-HPLC (column: Waters XBridge®C18, 19×150 mm, 5 μm; mobile phase A: water/0.5% NH₄HCO₃, mobile phaseB: acetonitrile; flow rate: 20 mL/minute; gradient: 30% B to 70% B in 10minutes; 254 nm) to provide the titled compound (4.4 mg, 5.96%).MS(ESI+) m/z 378.0 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 1.63 (d, 3H),2.30 (s, 3H), 2.45 (m, 2H), 3.94 (t, 2H), 4.34 (m, 3H), 5.77 (s, 1H),5.99 (s, 1H), 7.28 (d, 1H), 7.68 (d, 1H), 8.36 (s, 1H).

Example 9-6N-tert-butyl-2-[1-(5-chloropyridin-2-yl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-amine

7-Chloro-2-[1-(5-chloropyridin-2-yl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidine(80 mg, 0.260 mmol, INTERMEDIATE a9) was added to a solution of2-methylpropan-2-amine hydrochloride (285 mg, 2.60 mmol) andtriethylamine (79 mg, 0.781 mmol) in 1,4-dioxane (5 mL). The resultingmixture was stirred at 130° C. for 24 hours. This reaction mixture wasconcentrated under vacuum and the residue was purified bypreparative-HPLC (column: Waters XBridge® C18, 19×150 mm, 5 μm; mobilephase A: water/0.5% NH₄HCO₃, mobile phase B: acetonitrile; flow rate: 20mL/minute; gradient: 30% B to 70% B in 10 minutes; 254 nm) to providethe titled compound (55.2 mg, 61.6%). MS(ESI+) m/z 344.1 [M+H]⁺; ¹H NMR(400 MHz, CD₃OD) δ ppm 1.56 (s, 9H), 1.75 (d, 3H), 2.45 (s, 3H), 4.47(q, 1H), 6.15 (s, 1H), 6.18 (s, 1H), 7.37 (d, 1H), 7.77 (dd, 1H), 8.47(d, 1H).

Example 9-72-[1-(5-chloropyridin-2-yl)ethyl]-5-methyl-N-(1-methylcyclopropyl)pyrazolo[1,5-a]pyrimidin-7-amine

7-Chloro-2-[1-(5-chloropyridin-2-yl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidine(80 mg, 0.260 mmol, INTERMEDIATE a9) was added to a suspension of1-methylcyclopropanamine hydrochloride (140 mg, 1.302 mmol), potassiumiodide (43.2 mg, 0.260 mmol) and cesium carbonate (255 mg, 0.781 mmol)in 1,4-dioxane (5 mL). The resulting mixture was stirred at 130° C. for4 hours. This reaction mixture was concentrated under vacuum, and thecrude residue was purified by preparative-HPLC (column: Waters XBridge®C18, 19×150 mm, 5 μm; mobile phase A: water/0.05% NH₄HCO₃, mobile phaseB: acetonitrile; flow rate: 20 mL/minute; gradient: 30% B to 70% B in 10minutes; 254 nm) to provide the titled compound (22.1 mg, 24.8%).MS(ESI+) m/z 342.1 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 0.89 (m, 2H),0.98 (m, 2H), 1.51 (s, 3H), 1.77 (d, 3H), 2.50 (s, 3H), 4.50 (q, 1H),6.17 (s, 1H), 6.27 (s, 1H), 7.40 (d, 1H), 7.79 (dd, 1H), 8.49 (d, 1H).

Example 9-82-[1-(5-chloropyridin-2-yl)ethyl]-N-(3-fluorocyclobutyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-amine

7-Chloro-2-[1-(5-chloropyridin-2-yl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidine(100 mg, 0.326 mmol, INTERMEDIATE a9) was added to a suspension ofpotassium carbonate (135 mg, 0.977 mmol) and 3-fluorocyclobutanaminehydrochloride (49.1 mg 0.391 mmol) in N,N-dimethylformamide (2 mL). Thevessel was flushed with argon, and then the mixture was stirred andheated in a microwave (100° C., 300 W, 1 hour). The final mixture wasconcentrated under vacuum. The residue was purified by preparative-HPLC(column: Waters XBridge® C18 19×150; mobile phase A: water/10 mMNH₄HCO₃, mobile phase B: acetonitrile; flow rate: 25 mL/minute;gradient: 10% B to 60% B in 7 minutes; 254 nm) to provide the titledcompound (56.3 mg, 37%). MS(ESI+) m/z 360.1 [M+H]⁺; ¹H NMR (400 MHz,CD₃OD) δ ppm 1.78 (d, 3H), 2.50 (m, 1H), 2.59 (s, 3H), 2.76 (m, 1H),3.03 (m, 2H), 4.03 (m, 0.5H), 4.58 (q, 1H), 4.84 (m, 1H), 5.04 (m,0.5H), 6.35 (s, 1H), 6.36 (s, 1H), 7.43 (d, 1H), 7.80 (d, 1H), 8.50 (s,1H).

Example 9-92-[1-(5-chloropyridin-2-yl)ethyl]-5-methyl-7-(7-oxa-2-azaspiro[3.5]non-2-yl)pyrazolo[1,5-a]pyrimidine

7-Chloro-2-[1-(5-chloropyridin-2-yl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidine(100 mg, 0.326 mmol, INTERMEDIATE a9) was added to a suspension of7-oxa-2-azaspiro[3.5]nonane hydrochloride (63.9 mg, 0.391 mmol) andpotassium carbonate (135 mg, 0.977 mmol) in N,N-dimethylformamide (2mL). The vessel was flushed with argon, and then the mixture was stirredand heated in a microwave (100° C., 300 W, 1 hour). The final mixturewas concentrated under vacuum. The residue was purified bypreparative-HPLC (column: Waters XBridge® C18 19×150 mm, 5 μm; mobilephase A: water/10 mM NH₄HCO₃, mobile phase B: acetonitrile; flow rate:25 mL/minute; gradient: 10% B to 60% B in 7 minutes; 254 nm) to providethe titled compound (81 mg, 61.9%). MS(ESI+) m/z 398.1 [M+H]⁺; ¹H NMR(400 MHz, CD₃OD) δ ppm 1.75 (d, 3H), 1.92 (t, 4H), 2.49 (s, 3H), 3.32(s, 2H), 3.69 (t, 4H), 4.23 (s, 2H), 4.49 (q, 1H), 5.93 (s, 1H), 6.21(s, 1H), 7.43 (d, 1H), 7.82 (d, 1H), 8.49 (s, 1H).

Example 9-10N-[(3R)-1-{2-[1-(5-chloropyridin-2-yl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}pyrrolidin-3-yl]acetamide

7-Chloro-2-[1-(5-chloropyridin-2-yl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidine(80 mg, 0.260 mmol, INTERMEDIATE a9) was added to a suspension of(R)—N-(pyrrolidin-3-yl)acetamide (66.8 mg, 0.521 mmol) and potassiumcarbonate (108 mg, 0.781 mmol) in 1,4-dioxane (5 mL). The resultingmixture was stirred at 90° C. for 10 hours. This reaction mixture wasconcentrated under vacuum, and the residue was purified bypreparative-HPLC (column: Waters XBridge® C18, 19×150 mm, 5 m; mobilephase A: water/0.05% NH₄HCO₃, mobile phase B: acetonitrile; flow rate:20 mL/minute; gradient: 30% B to 70% B in 10 minutes; 254 nm) to providethe titled compound (31 mg, 29.8%). MS(ESI+) m/z 399.1 [M+H]⁺; ¹H NMR(400 MHz, CD₃OD) δ ppm 1.70 (d, 3H), 1.94 (s, 3H), 2.00 (m, 1H), 2.23(m, 1H), 2.35 (s, 3H), 3.95 (m, 3H), 4.18 (m, 1H), 4.45 (m, 2H), 5.76(s, 1H), 6.03 (s, 1H), 7.37 (d, 1H), 7.76 (dd, 1H), 8.44 (d, 1H).

Example 9-11N-[(3S)-1-{2-[1-(5-chloropyridin-2-yl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}pyrrolidin-3-yl]acetamide

7-Chloro-2-[1-(5-chloropyridin-2-yl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidine(100 mg, 0.326 mmol, INTERMEDIATE a9) was added to a suspension of(S)—N-(pyrrolidin-3-yl)acetamide (83 mg, 0.651 mmol) and potassiumcarbonate (135 mg, 0.977 mmol) in 1,4-dioxane (5 mL). The resultingmixture was stirred at 90° C. for 10 hours. This reaction mixture wasconcentrated under vacuum, and the residue was purified bypreparative-HPLC (column: Waters XBridge® C18, 19×150 mm, 5 m; mobilephase A: water/0.05% NH₄HCO₃, mobile phase B: acetonitrile; flow rate:20 mL/minute; gradient: 30% B to 70% B in 10 minutes; 254 nm) to providethe titled compound (19.8 mg, 15.2%). MS(ESI+) m/z 399.1 [M+H]⁺; ¹H NMR(400 MHz, CD₃OD) δ ppm 1.71 (d, 3H), 1.94 (s, 3H), 2.00 (m, 1H), 2.23(m, 1H), 2.36 (s, 3H), 3.97 (m, 3H), 4.19 (m, 1H), 4.46 (m, 2H), 5.77(s, 1H), 6.03 (s, 1H), 7.37 (d, 1H), 7.76 (dd, 1H), 8.44 (d, 1H).

Preparation of Compounds Derived from Intermediate a10 Example 10-1N-{(3R)-1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]pyrrolidin-3-yl}methanesulfonamide

Methanesulfonyl chloride (32.2 mg, 0.281 mmol) was added to a solutionof(3R)-1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]pyrrolidin-3-amine(80 mg, 0.234 mmol, INTERMEDIATE a10) and triethylamine (47.4 mg, 0.468mmol) in dichloromethane (10 mL). The mixture was stirred at roomtemperature for 1 hour. The final mixture was concentrated under vacuum.Purification of the residue by flash chromatography on silica gel elutedwith ethyl acetate/petroleum ether (gradient ethyl acetate:petroleumether from 0:1 to 1:1) provided the titled compound (38.0 mg, 38.7%).MS(ESI+) m/z 420.2 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 2.18 (m, 1H),2.39 (m, 1H), 2.53 (s, 3H), 3.04 (s, 3H), 3.32 (m, 4H), 4.13 (s, 2H),4.26 (m, 1H), 6.18 (s, 1H), 6.20 (s, 1H), 7.34 (m, 4H).

Preparation of Compounds Derived from Intermediate a11 Example 11-1N-{(3S)-1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidin-3-yl)}methanesulfonamideA

Methanesulfonyl chloride (35.4 mg, 0.309 mmol) was added dropwise to asolution of(3S)-1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidin-3-amine(100 mg, 0.281 mmol, INTERMEDIATE a11) and triethylamine (0.196 mL,1.405 mmol) in N,N-dimethylformamide (6 mL). The mixture was stirred atroom temperature for 1 hour and then concentrated under vacuum. Theresidue was purified by preparative-HPLC (column: Waters XBridge® C18,19×150 mm, 5 μm; mobile phase A: water/0.05% trifluoroacetic acid,mobile phase B: acetonitrile; flow rate: 20 mL/minute; gradient: 30% Bto 70% B in 10 minutes; 254 nm) to provide the titled compound as atrifluoroacetic acid salt (17.6 mg, 11.4%). MS(ESI+) m/z 434.1 [M+H]⁺;¹H NMR (400 MHz, CD₃OD) δ ppm 1.78 (m, 2H), 2.02 (m, 1H), 2.15 (m, 1H),2.53 (s, 3H), 2.99 (s, 3H), 3.70 (m, 1H), 3.81 (m, 2H), 4.13 (s, 2H),4.53 (m, 1H), 4.95 (m, 1H), 6.23 (s, 1H), 6.48 (s, 1H), 7.28 (m, 4H).

Preparation of Compounds Derived from Intermediate a12 Example 12-12-{1-[2-(3-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidin-2-yl}ethanol

A mixture of7-chloro-2-(3-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidine (80 mg,0.274 mmol, INTERMEDIATE a12), 2-(piperidin-2-yl)ethanol) (70.8 mg,0.548 mmol), and N-ethyl-N-isopropylpropan-2-amine (142 mg, 1.095 mmol)in ethanol (3 mL) were stirred at room temperature for 12 h and then at50° C. for 6 h.

For work-up, the reaction mixture was extracted with H₂O/CH₂Cl₂, and thecombined organic layers were washed with brine, dried over MgSO₄,filtered, and concentrated. After chromatographic purification using aTeledyne Isco CombiFlash® system (normal phase: 4 g column, eluent: 3-5%CH₃OH/CH₂Cl₂), the titled compound was obtained as clear oil (40 mg,38.0%). LC-MS (ESI+) m/z 385.2 [M+H]⁺; ¹H NMR (600 MHz, DMSO-d₆) δ ppm7.39 (t, J=1.8 Hz, 1H), 7.36-7.25 (m, 4H), 6.25 (s, 2H), 6.13 (s, 1H),4.99 (q, J=5.6, 5.0 Hz, 2H), 4.63 (t, J=5.2 Hz, 1H), 4.06 (s, 3H), 3.26(td, J=12.2, 2.9 Hz, 1H), 2.37 (s, 2H), 1.91-1.58 (m, 7H).

Determination of Biological Activity

Abbreviations: EGTA for ethylene glycol-bis(2-aminoethylether)-N,N,N′,N′-tetraacetic acid; GABA for γ-aminobutyric acid; GTPgS for guanosine5′-O-[gamma-thio]triphosphate; and Tris fortris(hydroxymethyl)aminomethane.

Preparation of Rat Brain Membranes for Native Receptor Assays

Membranes from rat brain cortex were prepared as described in detail byOlpe et al. and stored at concentrations of 1.66 mg/mL protein at −80°C. until required. (Olpe, H.-R, et al. Eur J Pharmacol 1990; 187:27-38).

[³⁵S] GTPgS Binding Assay

The composition of the assay mixtures [in a final volume of 200 μL in96-well U-bottom plates (Greiner) was as follows: 50 mM Tris-HCl buffer,pH 7.7, 10 mM MgCl₂, 0.2 mM EGTA, 2 mM CaCl₂, 100 mM NaCl, 20 Mguanosine 5′-diphosphate (Sigma), 0.3 nM [³⁵S]GTPgS (1250 Ci/mmol(PerkinElmer)), and the test compounds at increasing concentrations(from 10 nM up to 10 M), 10 g of rat cortical membranes, and aconcentration of 1 M GABA, that has been observed in previousexperiments to correspond to the EC₂₅, a concentration that gives 25% ofthe maximal response of GABA. The samples were incubated at roomtemperature for 60 minutes on a shaker. The incubation was stopped byrapid vacuum filtration over glass-fiber filter plates (UniFilter-96well, GF/B membrane plates, PerkinElmer) using a 96-well plate harvester(TOMTEK© Harvester). The UniFilter plate was washed five times withice-cold wash buffer (50 mM Tris-HCl buffer, pH 7.7, 10 mM MgCl₂, and100 mM NaCl. After filtration the plate was dried for 90 minutes at 55°C. The plates were closed on the bottom with black sealing membranes,and liquid scintillation cocktail (35 μL, Betaplate Scint, PerkinElmer)was added to each well. After sealing the top of the plate, anadditional incubation step of 90 minutes at room temperature followedbefore measuring the plate. The amount of membrane-bound [³⁵S]GTPgS wasmeasured using a 96-well plate reader (Microbeta®, PerkinElmer).Nonspecific binding was measured in the presence of unlabeled 10 μM ofGTPgS (Millipore) and without GABA. Basal binding was measured in theabsence of 1 μM GABA, and maximal binding was measured in the presenceof GABA using 1 mM GABA concentrations.

Data analysis. The concentration-response curves of compounds of thepresent disclosure in the presence of EC₂₅ of GABA-B receptor agonistwere generated using the GraphPad Prism® program (GraphPad Software, SanDiego, Calif.). Data was normalized using basal binding as 0% andmaximal binding as 100%. The curves were fitted by nonlinear regressionallowing determination of EC₅₀ values from sigmoidal dose-responsecurves. Each curve was performed using triplicate sample per date pointand 10 concentrations.

GTPgS Binding Example EC₅₀ (μM) 1-1  1.4 1-2  1.66 1-3  2.55 1-4  2.891-5  5.93 1-6  0.974 1-7  1.23 1-8  1.3 1-9  2.57 1-10 >10 1-11 >10 1-123.97 1-13 >10 1-14 1.03 1-15 1.18 1-16 >10 1-17 >10 1-18 2.69 1-19 101-20 2.15 1-21 1.38 2-1  0.118 2-2  0.435 2-3  0.508 2-4  0.128 2-5 0.146 2-6  0.242 2-7  0.185 2-8  0.071 2-9  0.604 2-10 0.152 2-11 0.0572-12 2.82 2-13 0.446 2-14 0.165 2-15 3.93 2-16 0.586 2-17 2.18 2-180.499 2-19 1.31 2-20 0.093 2-21 0.394 2-22 0.07 2-23 2.73 3-1  0.0083-2  0.014 4-1  0.005 4-2  0.009 5-1  0.003 5-2  0.007 6-1  1.82 7-1 1.08 8-1  >10 8-2  0.087 8-3  0.42 8-4  0.827 8-5  0.365 8-6  0.509 8-7 2 8-8  0.746 8-9  0.344 8-10 >10 8-11 0.378 8-12 0.37 8-13 2.55 8-140.593 8-15 0.57 8-16 2.18 8-17 0.76 8-18 0.746 8-19 0.274 8-20 0.5 8-210.561 8-22 0.771 9-1  1.54 9-2  1.6 9-3  2.02 9-4  0.628 9-5  1.66 9-6 0.798 9-7  1.32 9-8  9.3 9-9  >10 9-10 >10 9-11 >10 10-1  >10 11-1  3.5112-1  5.67

It is understood that the foregoing detailed description andaccompanying examples are merely illustrative and are not to be taken aslimitations upon the scope of the invention, which is defined solely bythe appended claims and their equivalents. Various changes andmodifications to the described embodiments will be apparent to thoseskilled in the art. Such changes and modifications, including withoutlimitation those relating to the chemical structures, substituents,derivatives, intermediates, syntheses, formulations, or methods, or anycombination of such changes and modifications of use of the invention,may be made without departing from the spirit and scope thereof.

What is claimed is:
 1. A compound of formula (I):

or a pharmaceutically acceptable salt or isotopically labeled formthereof, wherein: R¹ is selected from the group consisting ofC₁-C₆alkyl,C₃-C₆cycloalkyl and C₃-C₆cycloalkylC₁-C₆alkyl, wherein theC₁-C₆alkyl and the C₁-C₆alkyl of C₃-C₆cycloalkylC₁-C₆alkyl areunsubstituted or substituted with one or more substituents R^(1a)independently selected from the group consisting of C₁-C₆alkoxy,C₁-C₆alkylcarbonylamino, C₁-C₆alkylsulfonylamino, amido, carboxy, cyano,halogen, hydroxy, and oxo; and the C₃-C₆cycloalkyl and theC₃-C₆cycloalkyl of C₃-C₆cycloalkylC₁-C₆alkyl are unsubstituted orsubstituted with one or more substituents R^(1b) independently selectedfrom the group consisting of C₁-C₆alkoxy, C₁-C₆alkyl, amido,C₁-C₆alkylcarbonylamino, C₁-C₆alkylsulfonylamino, carboxy, cyano,halogen, haloC₁-C₆alkyl, hydroxy, hydroxyC₁-C₆alkyl, and oxo; R² isselected from the group consisting of hydrogen, C₁-C₆alkyl, andhaloC₁-C₆alkyl; or R¹, R² and the nitrogen to which they are attachedform a saturated 4-7-membered N-bound heterocycle, which in addition tothe nitrogen atom may have one further heteroatom selected from O, S andN as a ring member, wherein: each such 4-7-membered heterocycle isunsubstituted or substituted with one or more identical or differentsubstituents R^(1c), where R^(1c) is selected from the group consistingof C₁-C₆alkoxy, C₁-C₆alkyl, C₁-C₆alkylcarbonylamino,C₁-C₆alkylsulfonylamino, amido, carboxy, cyano, halogen, haloC₁-C₆alkyl,amino, hydroxy, hydroxyC₁-C₆alkyl, oxo, spirocyclic boundC₃-C₆cycloalkyl; and spirocyclic bound saturated 4-6-memberedheterocycle; wherein each spirocyclic bound C₃-C₆cycloalkyl andspirocyclic bound 4-6-membered heterocycle is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of C₁-C₆alkyl, cyano, halogen, haloC₁-C₆alkyl,hydroxy, and hydroxyC₁-C₆alkyl; R³ is hydrogen; R⁴ is C₁-C₆alkyl; L¹ is(CR⁵R⁶)_(m), wherein m is 1 and R⁵ and R⁶, are, at each occurrence,independently selected from the group consisting of hydrogen andC₁-C₆alkyl; and G¹ is selected from the group consisting ofC₅-C₁₀cycloalkyl, 5-6-membered heteroaryl, and phenyl; wherein eachC₅-C₁₀cycloalkyl, 5-6-membered heteroaryl, and phenyl is unsubstitutedor substituted with one or more identical or different substituentsR^(G), where R^(G) is selected from the group consisting of C₁-C₆alkyl,cyano, haloC₁-C₆alkyl, halogen, C₁-C₆alkoxy and haloC₁-C₆alkoxy.
 2. Thecompound or pharmaceutically acceptable salt of claim 1 wherein R⁵ ishydrogen and R⁶ is C₁-C₆alkyl.
 3. The compound or pharmaceuticallyacceptable salt of claim 1, wherein G¹ is selected from the groupconsisting of 5-6-membered heteroaryl and phenyl; wherein the5-6-membered heteroaryl and phenyl are unsubstituted or carry 1, 2, 3 or4 radicals R^(G).
 4. The compound or pharmaceutically acceptable salt ofclaim 1, wherein G¹ is selected from the group consisting of phenyl,3-chlorophenyl, 4-chlorophenyl, 4-(trifluoromethyl)phenyl, pyridine-2-yland 5-chloropyridin-2-yl.
 5. The compound or pharmaceutically acceptablesalt of claim 1, wherein: R¹ is selected from the group consisting ofC₁-C₆alkyl, C₃-C₆cycloalkyl and C₃-C₆cycloalkylC₁-C₆alkyl, wherein theC₁-C₆alkyl and the C₁-C₆alkyl of C₃-C₆cycloalkylC₁-C₆alkyl areunsubstituted or substituted with one or more substituents R^(1a); andthe C₃-C₆cycloalkyl, the C₃-C₆cycloalkyl of C₃-C₆cycloalkylC₁-C₆alkyl,4-7-membered heterocycle are unsubstituted or substituted with one ormore substituents R^(1b); and R² is selected from the group consistingof hydrogen, C₁-C₆alkyl, and haloC₁-C₆alkyl.
 6. The compound orpharmaceutically acceptable salt of claim 5, wherein: R¹ is C₁-C₆alkyl,wherein the C₁-C₆alkyl is unsubstituted or substituted with one or morehalogen atoms; and R² is hydrogen.
 7. The compound or pharmaceuticallyacceptable salt of claim 5, wherein: R¹ is selected from the groupconsisting of C₃-C₆cycloalkyl and C₃-C₆cycloalkylC₁-C₆alkyl, wherein theC₁-C₆alkyl of C₃-C₆cycloalkylC₁-C₆alkyl is unsubstituted or substitutedwith one or more substituents R^(1a), and the C₃-C₆cycloalkyl and theC₃-C₆cycloalkyl of C₃-C₆cycloalkylC₁-C₆alkyl are unsubstituted orsubstituted with one or more substituents R^(1b); and R² is selectedfrom the group consisting of hydrogen, C₁-C₆alkyl, and haloC₁-C₆alkyl.8. The compound or pharmaceutically acceptable salt of claim 1, wherein:R¹, R² and the nitrogen to which they are attached form a 4-7-memberedheterocycle selected from the group consisting of azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl,and azepanyl wherein azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, thiomorpholinyl, and azepanyl are unsubstituted or carry 1,2, 3 or 4 identical or different radicals R^(1c).
 9. The compound orpharmaceutically acceptable salt of claim 8, wherein: R¹, R² and thenitrogen to which they are attached form a 4-5-membered heterocycleselected from the group consisting of azetidinyl and pyrrolidinyl,wherein azetidinyl and pyrrolidinyl are unsubstituted or carry 1, 2, 3or 4 identical or different radicals R^(1c).
 10. The compound orpharmaceutically acceptable salt of claim 8, wherein: R¹, R² and thenitrogen to which they are attached form a 6-7-membered heterocycleselected from the group consisting of piperidinyl, piperazinyl, andazepanyl wherein piperidinyl, piperazinyl, and azepanyl areunsubstituted or carry 1, 2, 3 or 4 identical or different radicalsR^(1c).
 11. The compound or pharmaceutically acceptable salt of claim 1,wherein the moiety NR¹R² is selected from the group consisting ofazetidin-1-yl, 3-ethyl-2-carboxylazetidin-1-yl, pyrroldin-1-yl,3,3-difluoropyrrolidin-1-yl, 3-(acetylamino)pyrrolidin-1-yl,3-(methylsulfonylamino)pyrrolidin-1-yl, 3-aminocarbonylpyrrolidin-1-yl,piperidin-1-yl, 3-fluoropiperidin-1-yl, 4-fluoropiperidin-1-yl,2-(2-hydroxyethyl)piperidin-1-yl, 2-ethylpiperidin-1-yl,2-(hydroxymethyl)piperidin-1-yl, 3-(hydroxymethyl)piperidin-1-yl,2-oxopiperidin-1-yl, 3-(methylsulfonylamino)piperidin-1-yl,2-(2-hydroxyethyl)-3-oxopiperazin-1-yl, 3,3-difluorpiperidin-1-yl,3-hydroxypiperidin-1-yl, 4-hydroxy-3,3-difluoropiperidin-1-yl,2,2,2-trifluoroethylamino, tert-butylamino,1-(trifluoromethyl)-ethylamino, 1-methylcyclopropylamino,1-(trifluoromethyl)cyclopropylamino, 3-fluorocyclobutylamino,3,3-difluorocyclobutylamino, 3-hydroxycyclobutylamino,(3,3-difluorocyclobutyl)methylamino, 2-oxa-6-azaspiro[3.4]oct-6-yl,2-oxa-7-azaspiro-[3.5]non-7-yl, 7-oxa-2-azaspiro[3.5]non-2-yl and3-hydroxy-7-azaspiro[3.4]oct-7-yl.
 12. A compound, selected from thegroup consisting of:2-{1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidin-2-yl}ethanol;{1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidin-2-yl}methanol;2-(4-chlorobenzyl)-5-methyl-N-(1-methylcyclopropyl)pyrazolo[1,5-a]pyrimidin-7-amine;2-(4-chlorobenzyl)-7-(3,3-difluoropiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine;1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]-3,3-difluoropiperidin-4-ol;(3S)-1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidin-3-ol;(3R)-1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidin-3-ol;{(3S)-1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidin-3-yl}methanol;2-(4-chlorobenzyl)-5-methyl-7-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidine;1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidin-2-one;N-{(3R)-1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]pyrrolidin-3-yl}acetamide;2-(4-chlorobenzyl)-5-methyl-7-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine;7-(azetidin-1-yl)-2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidine;N-tert-butyl-2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-amine;2-(4-chlorobenzyl)-5-methyl-N-[1-(trifluoromethyl)cyclopropyl]pyrazolo[1,5-a]pyrimidin-7-amine;2-(4-chlorobenzyl)-5-methyl-N-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyrimidin-7-amine;N-{(3S)-1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]pyrrolidin-3-yl}acetamide;2-(4-chlorobenzyl)-5-methyl-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyrazolo[1,5-a]pyrimidin-7-amine;1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidine-3-carboxamide;2-(4-chlorobenzyl)-5-methyl-N-[(2R)-1,1,1-trifluoropropan-2-yl]pyrazolo[1,5-a]pyrimidin-7-amine;{(3R)-1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidin-3-yl}methanol;2-(1-{2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}piperidin-2-yl)ethanol;2-[1-(4-chlorophenyl)ethyl]-5-methyl-N-(1-methylcyclopropyl)pyrazolo[1,5-a]pyrimidin-7-amine;2-[1-(4-chlorophenyl)ethyl]-7-(3,3-difluoropyrrolidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine;2-[1-(4-chlorophenyl)ethyl]-7-(4-fluoropiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine;(1-{2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}piperidin-2-yl)methanol;2-[1-(4-chlorophenyl)ethyl]-7-(3-fluoropiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine;2-[1-(4-chlorophenyl)ethyl]-7-(3,3-difluoropiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine;N-tert-butyl-2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-amine;2-[1-(4-chlorophenyl)ethyl]-5-methyl-7-(2-oxa-7-azaspiro[3.5]non-7-yl)pyrazolo[1,5-a]pyrimidine;(3S)-1-{2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}piperidin-3-ol;(3R)-1-{2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}piperidin-3-ol;7-(azetidin-1-yl)-2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidine;2-[1-(4-chlorophenyl)ethyl]-5-methyl-7-(7-oxa-2-azaspiro[3.5]non-2-yl)pyrazolo[1,5-a]pyrimidine;2-[1-(4-chlorophenyl)ethyl]-N-(3-fluorocyclobutyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-amine;(2R,3R)-1-{2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}-3-ethylazetidine-2-carboxylicacid;2-[1-(4-chlorophenyl)ethyl]-N-[(3,3-difluorocyclobutyl)methyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-amine;N-[(3S)-1-{2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}pyrrolidin-3-yl]acetamide;cis-3-({2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}amino)cyclobutanol;trans-3-({2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}amino)cyclobutanol;6-{2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}-6-azaspiro[3.4]octan-1-ol;2-[1-(4-chlorophenyl)ethyl]-N-(3,3-difluorocyclobutyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-amine;2-[1-(4-chlorophenyl)ethyl]-7-[(2R)-2-ethylpiperidin-1-yl]-5-methylpyrazolo[1,5-a]pyrimidine;N-[(3R)-1-{2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}pyrrolidin-3-yl]acetamide;2-(1-{2-[1-(4-chlorophenyl)propyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}piperidin-2-yl)ethanol;2-[1-(4-chlorophenyl)propyl]-7-(3,3-difluoropiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine;2-(1-{2-[1-(4-chlorophenyl)-2-methylpropyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}piperidin-2-yl)ethanol;2-[1-(4-chlorophenyl)-2-methylpropyl]-7-(3,3-difluoropiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine;2-(1-{2-[1-(4-chlorophenyl)butyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}piperidin-2-yl)ethanol;2-[1-(4-chlorophenyl)butyl]-7-(3,3-difluoropiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine;2-(1-{5-methyl-2-[3-(trifluoromethyl)benzyl]pyrazolo[1,5-a]pyrimidin-7-yl}piperidin-2-yl)ethanol;2-{1-[5-methyl-2-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)pyrazolo[1,5-a]pyrimidin-7-yl]piperidin-2-yl}ethanol;(2S)-1-(5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)azetidine-2-carboxamide;2-[1-(5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)piperidin-2-yl]ethanol;5-methyl-7-(2-oxa-6-azaspiro[3.4]oct-6-yl)-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine;5-methyl-7-(7-oxa-2-azaspiro[3.5]non-2-yl)-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine;(3R)-1-(5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)piperidin-3-ol;N-(3-fluorocyclobutyl)-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-amine;N-[(3S)-1-(5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)pyrrolidin-3-yl]acetamide;5-methyl-N-(1-methylcyclopropyl)-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-amine;[1-(5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)piperidin-2-yl]methanol;(2S)-1-(5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)azetidine-2-carboxylicacid;7-(4-fluoropiperidin-1-yl)-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine;7-(3-fluoropiperidin-1-yl)-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine;3-(2-hydroxyethyl)-4-(5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)piperazin-2-one;N-[(3,3-difluorocyclobutyl)methyl]-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-amine;7-(3,3-difluoropyrrolidin-1-yl)-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine;N-[(3R)-1-(5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)pyrrolidin-3-yl]acetamide;7-(3,3-difluoropiperidin-1-yl)-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine;1-(5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)piperidin-2-one;N-tert-butyl-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-amine;N-(3,3-difluorocyclobutyl)-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-amine;5-methyl-7-(2-oxa-7-azaspiro[3.5]non-7-yl)-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine;1-(5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)pyrrolidine-3-carboxamide;(1-{2-[1-(5-chloropyridin-2-yl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}piperidin-3-yl)methanol;2-[1-(5-chloropyridin-2-yl)ethyl]-N-(3,3-difluorocyclobutyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-amine;(3S)-1-{2-[1-(5-chloropyridin-2-yl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}piperidin-3-ol;2-[1-(5-chloropyridin-2-yl)ethyl]-7-(3,3-difluoropiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine;2-[1-(5-chloropyridin-2-yl)ethyl]-7-(3,3-difluoropyrrolidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine;N-tert-butyl-2-[1-(5-chloropyridin-2-yl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-amine;2-[1-(5-chloropyridin-2-yl)ethyl]-5-methyl-N-(1-methylcyclopropyl)pyrazolo[1,5-a]pyrimidin-7-amine;2-[1-(5-chloropyridin-2-yl)ethyl]-N-(3-fluorocyclobutyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-amine;2-[1-(5-chloropyridin-2-yl)ethyl]-5-methyl-7-(7-oxa-2-azaspiro[3.5]non-2-yl)pyrazolo[1,5-a]pyrimidine;N-[(3R)-1-{2-[1-(5-chloropyridin-2-yl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}pyrrolidin-3-yl]acetamide;N-[(3S)-1-{2-[1-(5-chloropyridin-2-yl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}pyrrolidin-3-yl]acetamide;N-{(3R)-1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]pyrrolidin-3-yl}methanesulfonamide;N-{(3S)-1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidin-3-yl}methanesulfonamide;and2-{1-[2-(3-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidin-2-yl}ethanol,or a pharmaceutically acceptable salt thereof.
 13. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundor pharmaceutically acceptable salt of claim 1 in combination with apharmaceutically acceptable carrier.
 14. The compound ofpharmaceutically acceptable salt of claim 1, wherein: R¹ is selectedfrom the group consisting of C₁-C₆alkyl, C₃-C₆cycloalkyl andC₃-C₆cycloalkylC₁-C₆alkyl; wherein the C₁-C₆alkyl and the C₁-C₆alkyl ofC₃-C₆cycloalkylC₁-C₆alkyl are unsubstituted or substituted with one ormore substituents R^(1a) independently selected from the groupconsisting of cyano and halogen; and the C₃-C₆cycloalkyl and theC₃-C₆cycloalkylC₁-C₆alkyl are unsubstituted or substituted with one ormore substituents R^(1b) independently selected from the groupconsisting of C₁-C₆, cyano, halogen and haloC₁-C₆alkyl; R² is hydrogen;or R¹, R² and the nitrogen to which they are attached from a saturated4-6-membered N-bound heterocycle, which in addition to the nitrogen atommay have one further heteroatom selected from O and N as a ring member,wherein: each such 4-6-membered heterocycle is unsubstituted orsubstituted with one or more identical or different substituents R^(1c),where R^(1c) is selected from the group consisting of C₁-C₆alkyl,C₁-C₆alkylcarbonylamino, C₁-C₆alkylsulfonylamino, amido, carboxy, cyano,halogen, haloC₁-C₆alkyl, hydroxy, hydroxyC₁-C₆alkyl, oxo, spirocyclicbound C₃-C₆cycloalkyl; and spirocyclic bound saturated 4-6-memberedheterocycle; wherein each spirocyclic bound C₃-C₆cycloalkyl andspirocyclic bound 4-6-membered heterocycle is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of C₁-C₆alkyl, hydroxy, and hydroxyC₁-C₆alkyl; andG¹ is selected from the group consisting of C₅-C₁₀cycloalkyl,5-6-membered heteroaryl, and phenyl; wherein each C₅-C₁₀cycloalkyl, 5-6-membered heteroaryl, and phenyl is unsubstituted or substituted withone or more identical or different substituents R^(G), where R^(G) isselected from the group consisting of C₁-C₆alkyl, cyano, haloC₁-C₆alkyland halogen.